ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.658_659del (p.Val220fs)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.658_659del (p.Val220fs)
Variation ID: 9342 Accession: VCV000009342.88
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 13q13.1 13: 32329468-32329469 (GRCh38) [ NCBI UCSC ] 13: 32903605-32903606 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Aug 25, 2024 Apr 22, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.658_659del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Val220fs frameshift NM_000059.3:c.657_658del NM_000059.3:c.658_659delGT NC_000013.11:g.32329469_32329470del NC_000013.10:g.32903606_32903607del NG_012772.3:g.18990_18991del LRG_293:g.18990_18991del U43746.1:n.886_887delGT - Protein change
- Other names
- 886_887delGT
- 886delGT
- Canonical SPDI
- NC_000013.11:32329467:TGT:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18935 | 19094 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
|
Oct 29, 2021 | RCV000009932.16 | |
Pathogenic (1) |
no assertion criteria provided
|
Jan 1, 2007 | RCV000009929.13 | |
Pathogenic (2) |
criteria provided, single submitter
|
Oct 29, 2021 | RCV000009930.14 | |
risk factor (1) |
no assertion criteria provided
|
Jan 1, 2007 | RCV000009931.13 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000044988.29 | |
Pathogenic (14) |
reviewed by expert panel
|
Apr 22, 2016 | RCV000031637.30 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000131858.22 | |
Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000074548.59 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 2, 2020 | RCV000210073.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 26, 2024 | RCV000466729.12 | |
Pathogenic (2) |
no assertion criteria provided
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Jun 11, 2019 | RCV000735587.10 | |
Pathogenic (1) |
no assertion criteria provided
|
- | RCV001356991.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2021 | RCV001843452.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2021 | RCV002496316.8 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 21, 2023 | RCV003128126.8 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162226.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 25, 2023 | RCV003335024.2 | |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 22, 2016)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000282430.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
|
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Pathogenic
(Nov 18, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449833.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 3
|
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Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499761.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Oct 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000778635.2
First in ClinVar: Jun 23, 2018 Last updated: Jun 02, 2021 |
Comment:
PVS1, PM2, PP5
Number of individuals with the variant: 1
|
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Pathogenic
(Oct 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
inherited
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Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002103002.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
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Pathogenic
(Oct 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Wilms tumor 1
Affected status: unknown
Allele origin:
inherited
|
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002103006.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
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Pathogenic
(Oct 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Medulloblastoma
Affected status: unknown
Allele origin:
inherited
|
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002103005.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
|
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Pathogenic
(Oct 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
inherited
|
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002103003.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
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Pathogenic
(Oct 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial prostate cancer
Affected status: unknown
Allele origin:
inherited
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Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002103004.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
|
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Pathogenic
(Oct 06, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Department of Medical Genetics, Oslo University Hospital
Accession: SCV000605688.3
First in ClinVar: Sep 28, 2017 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV003802786.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
The BRCA2 c.658_659delGT (p.Val220IlefsTer4) variant results in the deletion of two nucleotides at position c.658-659, causing a shift in the protein reading frame that is … (more)
The BRCA2 c.658_659delGT (p.Val220IlefsTer4) variant results in the deletion of two nucleotides at position c.658-659, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, the c.658_659delGT variant, also referred to as c.886delGT, has been identified in a heterozygous state in at least eight individuals with breast cancer and one individual with ovarian cancer (PMID: 9667259; PMID: 23767878; PMID: 24504028; PMID: 27153395). The variant has also been observed in a compound heterozygous state in at least seven individuals with Fanconi anemia (PMID: 14670928; PMID: 26064523). The highest frequency of this allele in the Genome Aggregation Database is 0.000126 in the African/African-American population. Based on the available evidence the c.658_659delGT (p.Val220IlefsTer4) variant is classified as pathogenic for hereditary breast and ovarian cancer. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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BRCA2-related disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046239.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This frameshifting variant in exon 8 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more)
This frameshifting variant in exon 8 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in individuals with breast and ovarian cancer (PMID: 22923021, 23767878, 28324225). This variant has also been reported as a compound heterozygous change in patients with Fanconi anemia (PMID: 16825431). Loss-of-function variation in BRCA2 is an established mechanism of disease (PMID: 20104584). The c.658_659del (p.Val220IlefsTer4) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (13/276414) and thus is presumed to be rare. Based on the available evidence, the c.658_659del (p.Val220IlefsTer4) variant is classified as Pathogenic. (less)
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Pathogenic
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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BRCA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000805748.2
First in ClinVar: Jun 23, 2018 Last updated: Nov 20, 2023 |
Comment:
The BRCA2 c.658_659delGT variant is predicted to result in a frameshift and premature protein termination (p.Val220Ilefs*4). This variant is alternatively described as c.658delGT, c.886delGT or … (more)
The BRCA2 c.658_659delGT variant is predicted to result in a frameshift and premature protein termination (p.Val220Ilefs*4). This variant is alternatively described as c.658delGT, c.886delGT or c.886_887delGT. This variant has been observed in individuals with personal and family histories of breast and/or ovarian cancer (Novakovic et al. 2012. PMID: 22923021; Berzina et al. 2013. PMID: 23767878; Tung et al. 2016. PMID: 26976419), Fanconi anemia (group D1), and other types of malignancies, including brain tumors (Offit et al. 2003. PMID: 14559878; Reid et al. 2005. PMID: 15689453; Alter et al. 2006, PMID: 16825431). This variant, in combination with another variant in the same or a different gene, has also been reported in individuals with multiple malignancies including colorectal cancer (Heidemann et al. 2012. PMID: 22535016; Degrolard-Courcet et al. 2014, PMID: 24301060). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32903604-CTG-C). In ClinVar, it has been classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/9342). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003814404.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Dec 29, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934294.2
First in ClinVar: Sep 25, 2021 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PVS1,PM5_STR
Clinical Features:
Family history of cancer (present)
Sex: female
|
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Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000073001.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val220Ilefs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Val220Ilefs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs768580992, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 26657402). This variant is also known as 886delGT. ClinVar contains an entry for this variant (Variation ID: 9342). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000292146.5
First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 8 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more)
This variant deletes 2 nucleotides in exon 8 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 886delGT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 27153395, 28324225, 28724667, 30287823). It has also been observed in compound heterozygous state with a pathogenic variant in two individuals affected with Fanconi anemia (PMID: 16825431). This variant has been identified in 13/276414 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
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Pathogenic
(Nov 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000605780.3
First in ClinVar: Aug 05, 2017 Last updated: Apr 20, 2024 |
Comment:
The p.Val220IlefsX4 variant in BRCA2 has been identified in >50 individuals with BRCA2-associated cancers (Frank 1998 PMID:9667259, Berzina 2013 PMID:23767878, Breast Cancer Information Core (BIC) … (more)
The p.Val220IlefsX4 variant in BRCA2 has been identified in >50 individuals with BRCA2-associated cancers (Frank 1998 PMID:9667259, Berzina 2013 PMID:23767878, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/) and in 3 compound heterozygous individuals with Fanconi anemia (Offit 2003 PMID:14559878, Hirsch 2004 PMID:14670928, Reid 2005 PMID:15689453). It has also been identified in 0.012% (5/41438) of African/African American chromosomes and in 0.003% (2/68004) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 220 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 9342). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1. (less)
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247635.24
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Comment:
BRCA2: PVS1, PS3:Moderate, PS4:Supporting
Number of individuals with the variant: 8
|
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Pathogenic
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266043.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
bilateral breast cancer (present)
Age: 50-59 years
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 50-59 years
|
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Pathogenic
(Nov 03, 2014)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Michigan Medical Genetics Laboratories, University of Michigan
Accession: SCV000195951.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
Tissue: Blood
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Pathogenic
(Jul 10, 2014)
|
criteria provided, single submitter
Method: research
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584073.1 First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016 |
Number of individuals with the variant: 1
|
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Pathogenic
(Sep 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744390.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447718.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Breast carcinoma (present)
Sex: female
|
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Pathogenic
(Feb 10, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002536247.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.658_659delGT (p.V220Ifs*4) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancer (PMID: 29446198, 9667259, 33478551, 27741520, 31112363, … (more)
The BRCA2 c.658_659delGT (p.V220Ifs*4) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancer (PMID: 29446198, 9667259, 33478551, 27741520, 31112363, 32875559, 23767878, 32098980). This variant has also been reported in compound heterozygosity in several individuals with Fanconi anemia, complementation group D1 (PMID: 14670928, 26657402). It is also known as c.886_887delGT and c.886delGT in the literature. This variant is a well-established pathogenic variant associated with hereditary breast and ovarian cancer syndrome (PMID: 29446198 ). This variant causes a frameshift at amino acid 220 that results in premature termination 4 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in BRCA1 or BRCA2 are known to be pathogenic (PMID: 29446198). This variant was observed in 3/23770 chromosomes in the African/African American population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000327465.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
|
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Pathogenic
(Apr 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000494408.2
First in ClinVar: Sep 04, 2016 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The c.658_659delGT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known … (more)
Variant summary: The c.658_659delGT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.755_758delACAG, p.Asp252fsX24; c.771_775delTCAAA, p.Asn257fsX17; c.778_779delGA, p.Glu260fsX15). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in numerous affected individuals in the literature, including 2 siblings affected with Fanconi anemia who also carried a second pathogenic BRCA2 variant (Svojgr_2016). Mutliple reputable clinical labs have classified the variant as "Pathogenic". Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Feb 04, 2015)
|
criteria provided, single submitter
Method: literature only
|
Breast-ovarian cancer, familial 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000221117.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Oct 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002812445.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000108633.14
First in ClinVar: Dec 10, 2013 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in the heterozygous state in individuals from hereditary breast and ovarian cancer families (Frank 1998, Jakubowska 2003, Machado 2007, Berzina 2013, Cunningham 2014, de Juan 2015); Observed in the compound heterozygous state with a second pathogenic BRCA2 variant in patients with Fanconi anemia (Alter 2007, Miele 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 886delGT; This variant is associated with the following publications: (PMID: 9667259, 14647210, 15689453, 27836010, 26681312, 30128899, 17513806, 23767878, 24504028, 26026974, 16825431, 26064523, 26779294, 24528374, 26843898, 22535016, 27376475, 27153395, 26657402, 27831900, 14559878, 14670928, 28724667, 28324225, 28166811, 22009639, 29339979, 29753700, 29492181, 30078507, 29310832, 30350268, 30630528, 30122538, 30720243, 29790872, 29575201, 30093976, 31411802, 31396961, 31263054, 31957001, 27741520, 29625052, 26689913, 32318955, 31447099, 31980526, 31948886, 34008015, 32467295, 31589614, 32341426, 31825140, 32719484, 30787465) (less)
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Pathogenic
(Mar 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296738.7
First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024 |
Comment:
This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this … (more)
This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35220195 (2022), 33478551 (2021), 32438681 (2020), 32098980 (2020), 32341426 (2020), 32318955 (2020), 31980526 (2020), 31957001 (2020), 31411802 (2019), 31263054 (2019), 30350268 (2018), 30287823 (2018), 29492181 (2018)). Additionally, the variant has been reported in individuals with prostate cancer (PMIDs: 31948886 (2020), 32875559 (2020)), colorectal cancer (PMID: 26681312 (2015)), mesothelioma (PMID: 34008015 (2021), and esophageal squamous cell carcinoma (PMID: 31396961 (2020)). The variant has occurred with an additional pathogenic BRCA2 variant in children with Fanconi Anemia, Wilm's tumor, and/or medulloblastoma (PMIDs: 29753700 (2018), 26657402 (2016), 26064523 (2015), 16825431 (2007), 15689453 (2005), 14670928 (2004)). The frequency of this variant in the general population, 0.00013 (3/23770 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049181.5
First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024 |
Comment:
The BRCA2 c.658_659delGT; p.Val220IlefsTer4 variant (rs80359604), also known as 886delGT, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer … (more)
The BRCA2 c.658_659delGT; p.Val220IlefsTer4 variant (rs80359604), also known as 886delGT, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer syndrome (Cunningham 2014, de Juan 2015, Frank 1998, Heramb 2018), and in patients with Fanconi anemia when found in-trans with another pathogenic variant (Hirsch 2004, Svojgr 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 9342), and is found in the African/African American population with an allele frequency of 0.013% (3/23,770 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Val220IlefsTer4 variant is considered to be pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 4:4026. PMID: 24504028. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 14(4):505-13. PMID: 26026974. Frank T et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 16(7):2417-25. PMID: 9667259. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Hirsch B et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004 103(7):2554-9. PMID: 14670928. Svojgr K et al. Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children. Eur J Med Genet. 2016 59(3):152-7. PMID: 26657402. (less)
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004846802.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.658_659delGT (p.Val220Ilefs*4) variant in the BRCA2 gene is located on the exon 8 and is predicted to cause reading frame shift that introduces a … (more)
The c.658_659delGT (p.Val220Ilefs*4) variant in the BRCA2 gene is located on the exon 8 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Val220Ilefs*4), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 11897832). This c.658_659delGT variant was reported in more than 10 unrelated individuals with ovarian/breast cancer (PMID: 33478551, 34097676, 33670479, 32571290, 32824581, 22923021). It is one of the most frequently observed BRCA2 variants in North America and Lithuania, and more than 20 families were reported with the variant and disease (PMID: 29446198). This variant is reported in ClinVar as pathogenic (ID: 9342) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (13/276414). Therefore, the c.658_659delGT (p.Val220Ilefs*4) variant of BRCA2 has been classified as pathogenic. (less)
Number of individuals with the variant: 13
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Pathogenic
(Nov 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186913.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.658_659delGT pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of 2 nucleotides at positions 658 to 659, … (more)
The c.658_659delGT pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of 2 nucleotides at positions 658 to 659, causing a translational frameshift with a predicted alternate stop codon (p.V220Ifs*4). This mutation has been described in numerous HBOC families (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Berzina D et al. BMC Med. Genet. 2013;14:61; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). This mutation has also been observed in Fanconi anemia group D1 patients and was associated with brain tumors (medulloblastomas and glioblastomas) and Wilms tumor in these patients (Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9; Miele E et al. Biomark Res. 2015;3:13). Of note, this alteration is also designated as 886delGT in some published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. (less)
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Pathogenic
(Feb 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV000540998.2
First in ClinVar: Apr 17, 2017 Last updated: Jun 17, 2024 |
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196833.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline,
unknown
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147427.2
First in ClinVar: Apr 01, 2014 Last updated: Mar 29, 2015 |
Observation 1:
Number of individuals with the variant: 7
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 3:
Number of individuals with the variant: 7
Ethnicity/Population group: Central/Eastern European
Observation 4:
Number of individuals with the variant: 3
Ethnicity/Population group: Latin American, Caribbean
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean, Hispanic
Observation 6:
Number of individuals with the variant: 17
Ethnicity/Population group: Western European
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: Latino
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587560.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733216.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Dec 04, 2016)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000863725.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552307.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA2 p.Val220Ilefs*4 variant was identified in 19 of 19400 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Bayraktar 2012, … (more)
The BRCA2 p.Val220Ilefs*4 variant was identified in 19 of 19400 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Bayraktar 2012, Berzina 2013, Frank 1998, Heidemann 2012, Janavicius 2014, Novakovic 2012). The variant was also identified in the case study in two siblings with Fanconi anemia with biallelic FANCD1/BRCA2 mutations (Svojgr 2016). The variant was also identified in dbSNP (ID: rs80359604) as “With Pathogenic allele”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seventeen other submitters), LOVD 3.0 (58X as pathogenic), and in UMD-LSDB (30X as causal). This mutation was found at a high frequency in the Lithuanian population and could represent a Baltic founder mutation (Janavicius 2014).The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.658_659del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 220 and leads to a premature stop codon at position 223. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in BRCA associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(Jan 04, 2014)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000054244.6
First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2016 |
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Pathogenic
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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FANCONI ANEMIA, COMPLEMENTATION GROUP D1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030150.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more)
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
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Pathogenic
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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WILMS TUMOR
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030151.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more)
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
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risk factor
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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GLIOMA SUSCEPTIBILITY 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030152.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more)
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
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Pathogenic
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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MEDULLOBLASTOMA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030153.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more)
Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
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Pathogenic
(Jun 11, 2019)
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no assertion criteria provided
Method: case-control, clinical testing
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Breast and/or ovarian cancer
Affected status: no, yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV001451877.1
First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020 |
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
Observation 2:
Number of individuals with the variant: 6
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(-)
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no assertion criteria provided
Method: literature only
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Center for Precision Medicine, Meizhou People's Hospital
Accession: SCV002520927.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
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Pathogenic
(Aug 26, 2022)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV002588849.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758326.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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Pathogenic
(Feb 21, 2023)
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no assertion criteria provided
Method: clinical testing
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Uterine corpus cancer
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV003804356.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey. | Bora E | Cancer genetics | 2022 | PMID: 35220195 |
[Germline and Somatic Mutations in Archived Breast Cancer Specimens of Different Subtypes]. | Abramov IS | Molekuliarnaia biologiia | 2021 | PMID: 34097676 |
Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors. | Cheung M | Human molecular genetics | 2021 | PMID: 34008015 |
Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer. | Łukomska A | Cancers | 2021 | PMID: 33670479 |
BRCA1 and BRCA2 mutations in ovarian cancer patients from Belarus: update. | Savanevich A | Hereditary cancer in clinical practice | 2021 | PMID: 33478551 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Prevalence of BRCA1/BRCA2 pathogenic variation in Chinese Han population. | Dong H | Journal of medical genetics | 2021 | PMID: 32467295 |
Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland. | Wokołorczyk D | International journal of cancer | 2020 | PMID: 32875559 |
Prevalence of Recurrent Mutations Predisposing to Breast Cancer in Early-Onset Breast Cancer Patients from Poland. | Rogoża-Janiszewska E | Cancers | 2020 | PMID: 32824581 |
Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
Multiple primary tumors: a case report and review of the literature. | Zhao Z | BMC musculoskeletal disorders | 2020 | PMID: 32571290 |
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. | De Talhouet S | Scientific reports | 2020 | PMID: 32341426 |
Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women. | Zeng C | Breast cancer research and treatment | 2020 | PMID: 32318955 |
Oncologist-led BRCA 'mainstreaming' in the ovarian cancer clinic: A study of 255 patients and its impact on their management. | Rumford M | Scientific reports | 2020 | PMID: 32098980 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients. | Meng H | International journal of cancer | 2020 | PMID: 31957001 |
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. | Wu Y | European urology oncology | 2020 | PMID: 31948886 |
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients. | Gao X | Human mutation | 2020 | PMID: 31825140 |
BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese. | Ko JM | International journal of cancer | 2020 | PMID: 31396961 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
BRCA mutation frequency and clinical features of ovarian cancer patients: A report from a Chinese study group. | Bu H | The journal of obstetrics and gynaecology research | 2019 | PMID: 31411802 |
Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer. | Petridis C | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2019 | PMID: 31263054 |
BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry. | Friebel TM | Human mutation | 2019 | PMID: 31112363 |
Toward automation of germline variant curation in clinical cancer genetics. | Ravichandran V | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30787465 |
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering. | Soussi T | Human mutation | 2019 | PMID: 30720243 |
Population and breast cancer patients' analysis reveals the diversity of genomic variation of the BRCA genes in the Mexican population. | Fernández-Lopez JC | Human genomics | 2019 | PMID: 30630528 |
Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea. | Ryu JM | Breast cancer research and treatment | 2019 | PMID: 30350268 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. | Sapp JC | American journal of human genetics | 2018 | PMID: 30122538 |
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
Genomic sequencing identifies secondary findings in a cohort of parent study participants. | Thompson ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29790872 |
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. | Waszak SM | The Lancet. Oncology | 2018 | PMID: 29753700 |
Frequency of BRCA1 and BRCA2 causative founder variants in ovarian cancer patients in South-East Poland. | Kluz T | Hereditary cancer in clinical practice | 2018 | PMID: 29492181 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. | Heramb C | Hereditary cancer in clinical practice | 2018 | PMID: 29339979 |
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. | Sun J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28724667 |
Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. | Meisel C | Archives of gynecology and obstetrics | 2017 | PMID: 28324225 |
Aggregate penetrance of genomic variants for actionable disorders in European and African Americans. | Natarajan P | Science translational medicine | 2016 | PMID: 27831900 |
Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. | Fernandes GC | Oncotarget | 2016 | PMID: 27741520 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children. | Svojgr K | European journal of medical genetics | 2016 | PMID: 26657402 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup. | Miele E | Biomarker research | 2015 | PMID: 26064523 |
BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. | de Juan I | Familial cancer | 2015 | PMID: 26026974 |
Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania. | Janavičius R | Cancer genetics | 2014 | PMID: 25066507 |
Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. | Cunningham JM | Scientific reports | 2014 | PMID: 24504028 |
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. | Tea MK | Maturitas | 2014 | PMID: 24156927 |
BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families. | Berzina D | BMC medical genetics | 2013 | PMID: 23767878 |
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families. | Novaković S | International journal of oncology | 2012 | PMID: 22923021 |
Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. | Kim H | Breast cancer research and treatment | 2012 | PMID: 22798144 |
Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. | Heidemann S | Breast cancer research and treatment | 2012 | PMID: 22535016 |
Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. | Bayraktar S | Cancer | 2012 | PMID: 22009639 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. | Palma MD | Cancer research | 2008 | PMID: 18703817 |
BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. | Thomassen M | Acta oncologica (Stockholm, Sweden) | 2008 | PMID: 18465347 |
Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes. | Machado PM | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2007 | PMID: 17513806 |
Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. | Alter BP | Journal of medical genetics | 2007 | PMID: 16825431 |
Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. | Malone KE | Cancer research | 2006 | PMID: 16912212 |
Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. | Reid S | Journal of medical genetics | 2005 | PMID: 15689453 |
Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. | Hirsch B | Blood | 2004 | PMID: 14670928 |
A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer. | Jakubowska A | European journal of human genetics : EJHG | 2003 | PMID: 14647210 |
Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. | Offit K | Journal of the National Cancer Institute | 2003 | PMID: 14559878 |
BRCA2 gene mutations in families with aggregations of breast and stomach cancers. | Jakubowska A | British journal of cancer | 2002 | PMID: 12373604 |
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. | Hamann U | Journal of medical genetics | 2002 | PMID: 11897832 |
Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. | Frank TS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 1998 | PMID: 9667259 |
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HelpRecord last updated Aug 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.