ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7007G>A (p.Arg2336His)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7007G>A (p.Arg2336His)
Variation ID: 38077 Accession: VCV000038077.76
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32346896 (GRCh38) [ NCBI UCSC ] 13: 32921033 (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 Apr 1, 2014 May 1, 2024 Jun 18, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7007G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg2336His missense NC_000013.11:g.32346896G>A NC_000013.10:g.32921033G>A NG_012772.3:g.36417G>A LRG_293:g.36417G>A LRG_293t1:c.7007G>A LRG_293p1:p.Arg2336His U43746.1:n.7235G>A - Protein change
- R2336H
- Other names
- p.R2336H:CGC>CAC
- 7235G>A
- 7235G-A
- Canonical SPDI
- NC_000013.11:32346895:G:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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 |
18734 | 18892 |
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/Likely pathogenic (3) |
no assertion criteria provided
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Apr 1, 2023 | RCV000009923.14 | |
Pathogenic (12) |
reviewed by expert panel
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Jun 18, 2019 | RCV000031659.29 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000045112.26 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2023 | RCV000131031.20 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Sep 14, 2023 | RCV000174440.29 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2017 | RCV000475925.9 | |
Pathogenic (2) |
no assertion criteria provided
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Jun 11, 2019 | RCV000735595.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2021 | RCV002496486.8 |
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
(Jun 18, 2019)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV001161652.2
First in ClinVar: Feb 16, 2020 Last updated: Jan 07, 2023 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999037 (less)
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Pathogenic
(Feb 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000541005.1
First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 23, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002536290.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.7007G>A (p.R2336H) variant has been reported in heterozygosity in at least 30 individuals with breast and/or ovarian cancer (PMID: 25186627, 28294317, 30825404, 2661312, … (more)
The BRCA2 c.7007G>A (p.R2336H) variant has been reported in heterozygosity in at least 30 individuals with breast and/or ovarian cancer (PMID: 25186627, 28294317, 30825404, 2661312, 29161300) and Fanconi anemia (PMID 21719596, 12065746, 26968956). Functional studies have shown that this variant alters the splicing resulting in skipping of exon 13 (PMID: 20215541, 21719596, 22505045). It is also known as 7235G>A in the literature. This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 38077). Two different pathogenic changes at this position, c.7007G>T and c.7007G>C, have also been reported in individuals affected with breast and/or ovarian cancer (PMID: 30078507, 31782247, 31742824, 29446198, 32341426). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 21, 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
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744505.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Pathogenic
(Jun 20, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000225746.5
First in ClinVar: Jun 29, 2015 Last updated: Sep 28, 2017 |
Sex: mixed
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139167.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
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Pathogenic
(Jul 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695022.2
First in ClinVar: Dec 26, 2017 Last updated: Aug 08, 2020 |
Comment:
Variant summary: BRCA2 c.7007G>A (p.Arg2336His) alters a conserved last nucleotide located within exon 13 comprising the exonic splice region. At the protein level, it results … (more)
Variant summary: BRCA2 c.7007G>A (p.Arg2336His) alters a conserved last nucleotide located within exon 13 comprising the exonic splice region. At the protein level, it results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes splicing through the canonical 5' splicing donor site. Several publications report experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 13 (example, Sanz_2010, Thomassen_2006, Claes_2004). The variant was absent in 247772 control chromosomes. c.7007G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and Fanconi Anemia (example, Sanz_2010, Thomassen_2006, Konstantopoulou_2008, Ahmad_2012, Biswas_2011, Beristain_2010, Brooks_2006, Ghazwani_2016, Gorski_2004, Peixoto_2014, Siraj_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an inability to rescue the lethality of BRCA2-null mouse embryonic stem cells (Biswas_2011). Fourteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=14)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 06, 2018)
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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:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368474.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP1.
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Pathogenic
(Jun 30, 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: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000677695.2
First in ClinVar: Jan 06, 2018 Last updated: Dec 24, 2022 |
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Pathogenic
(Oct 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Malignant tumor of prostate 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: SCV002806006.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 15, 2023)
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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: SCV000210411.17
First in ClinVar: Feb 24, 2015 Last updated: Aug 24, 2023 |
Comment:
Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing, producing transcripts skipping exons 13 and exons 12-13, which lead … (more)
Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing, producing transcripts skipping exons 13 and exons 12-13, which lead to protein truncation or nonsense-mediated decay (Thomassen et al., 2006; Sanz et al., 2010; Biswas et al., 2011; Mesman et al., 2020); Observed in individuals with personal or family history of BRCA2-related cancers (Martin et al., 2001; Coppa et al., 2014; Bu et al., 2016; Lang et al., 2017; Kowalik et al., 2018; Fanale et al., 2020); Observed in the compound heterozygous or homozygous state in individuals with Fanconi anemia (Howlett et al., 2002; Degrolard-Courcet et al., 2014; Ghazwani et al., 2016); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing.; Also known as 7235G>A; This variant is associated with the following publications: (PMID: 16115142, 15645491, 25556971, 27884173, 28477318, 28541631, 11304778, 29310832, 34290354, 32438681, 15026808, 28888541, 33754277, 31558676, 31921681, 29176636, 20215541, 18489799, 22505045, 22486713, 24301060, 21719596, 18451181, 16825431, 16792514, 25395318, 26968956, 27082205, 28294317, 28503720, 28476184, 17924331, 29297111, 28152038, 29907814, 28724667, 25186627, 29084914, 29387975, 30040829, 29565420, 15356654, 12065746, 32854451, 32398771, 33293522, 30214071, 29446198, 30825404, 31065452, 31131967, 34026625, 31825140, 31589614, 32719484, 32853339, 30787465, 35886069, 35494038, 34515413, 34178674, 35382848) (less)
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Pathogenic
(Apr 26, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226610.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP5, PM2, PM3, PS3, PS4_moderate
Number of individuals with the variant: 1
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Pathogenic
(Jul 14, 2022)
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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: SCV003814338.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000073125.14
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2336 of the BRCA2 protein (p.Arg2336His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2336 of the BRCA2 protein (p.Arg2336His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer, Fanconia anemia, and acute myelogenous leukemia (PMID: 12065746, 16115142, 22430266, 22486713, 25395318, 26968956). This variant is also known as 7235G>A. ClinVar contains an entry for this variant (Variation ID: 38077). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 27124784). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exons 12 and/or 13 and introduces a premature termination codon (PMID: 16792514, 20215541, 22505045; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.7007G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9150172, 9536098, 17576681, 20960228, 21548014, 22399190, 22505045). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 03, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000689020.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant alters the conserved, last nucleotide c.G of exon 13 of the BRCA2 gene and is predicted to affect RNA splicing. This variant is … (more)
This variant alters the conserved, last nucleotide c.G of exon 13 of the BRCA2 gene and is predicted to affect RNA splicing. This variant is also known as p.Arg2336His based on predicted change at the protein level. RNA studies have shown that this variant causes the out-of-frame skipping for exon 13 and exons 12 and 13 in carrier RNA (PMID: 16792514, 18489799, 20215541, 22505045). This variant has also been shown to poorly rescue BRCA2 deficiency and confer hypersensitivity to DNA damaging agents in mouse embryonic stem cells (PMID: 21719596). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 16792514, 20215541, 22505045, 30192042), and the variant is reported to cosegregate with disease with a likelihood ratio of 48.5651 (PMID: 31131967). This variant has also been observed in individuals affected with Fanconi anemia in compound heterozygosity with a pathogenic BRCA2 variant (PMID: 12065746, 24301060) or in homozygosity (PMID: 26968956). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 14, 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: SCV001159457.2
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The BRCA2 c.7007G>A; p.Arg2336His variant (rs28897743) is reported in the literature in individuals affected with breast and/or ovarian cancer and Fanconi anemia (Ahmad 2012, Coppa … (more)
The BRCA2 c.7007G>A; p.Arg2336His variant (rs28897743) is reported in the literature in individuals affected with breast and/or ovarian cancer and Fanconi anemia (Ahmad 2012, Coppa 2014, Fanale 2020, Ghazwani 2016). This variant is also reported in ClinVar (Variation ID: 38077) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant occurs in the last nucleotide of exon 13, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with this, transcript analyses demonstrate skipping of exon 13 or exons 12 and 13 in patient cells carrying this variant (Biswas 2011, Houdayer 2012, Sanz 2010). Based on the above information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Ahmad J et al. Detection of BRCA1/2 mutations in breast cancer patients from Thailand and Pakistan. Clin Genet. 2012 Dec;82(6):594-8. PMID: 22486713. Biswas K et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood. 2011 Sep 1;118(9):2430-42. PMID: 21719596. Coppa A et al. Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14. Breast Cancer Res Treat. 2014 Dec;148(3):629-35. PMID: 25395318. Fanale D et al. Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2. Cancers (Basel). 2020 Aug 25;12(9):2415. PMID: 32854451. Ghazwani Y et al. Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. Cancer Genet. 2016 Apr;209(4):171-6. PMID: 26968956. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. PMID: 22505045. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. PMID: 20215541. (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804680.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(May 11, 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: SCV000185961.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.7007G>A pathogenic mutation (also known as p.R2336H), located in coding exon 12 of the BRCA2 gene, results from a G to A substitution at … (more)
The c.7007G>A pathogenic mutation (also known as p.R2336H), located in coding exon 12 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7007. This changes the amino acid at codon 2336 from arginine to histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This mutation has been identified in multiple families affected with breast and/or ovarian cancer (Claes K et al Br .J. Cancer. 2004 Mar;90:1244-51; Machackova E et al. BMC Cancer. 2008 May;8:140; Ahmad J et al. Clin. Genet. 2012 Dec;82:594-8; Coppa A et al. Breast Cancer Res. Treat. 2014 Dec;148:629-35; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620; Fanale D et al. Cancers (Basel) 2020 Aug;12(9)). This mutation has also been reported in both a homozygous and compound heterozygous state in individuals diagnosed with Fanconi Anemia and AML (Barber LM et al. Br. J. Haematol. 2005 Sep;130:796-7; Ghazwani Y et al. Cancer Genet 2016 Apr;209(4):171-6). In addition, the c.7007G>A mutation has been shown to result in a deletion of exon 13 from the mRNA transcript, causing a frameshift and a premature stop codon in exon 14 (Ambry internal data; Farrugia D et al. Cancer Res. 2008 May;68:3523-31; Thomassen M et al. Genet. Test. 2006 Summer;10:116-20; Biswas K et al. Blood. 2011 Sep;118:2430-42; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et a. Hum. Mutat. 2012 Aug;33:1228-38). A multifactorial likelihood ratio analysis that included co-segregation, tumor pathology, co-occurrence and family history data determined this alteration to be pathogenic (Parsons MT et al. Hum Mutat 2019 09;40(9):1557-1578). Of note, this alteration is also designated as 7235G>A in published literature. Based on the supporting evidence, this alteration is interpreted 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
(Oct 02, 2015)
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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: SCV000327565.4
First in ClinVar: Sep 27, 2014 Last updated: Dec 11, 2022 |
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Pathogenic
(Jun 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003932753.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
A known pathogenic mutation was detected in the BRCA2 gene. This sequence change replaces arginine with histidine at codon 2336 of the BRCA2 protein (p.Arg2336His). … (more)
A known pathogenic mutation was detected in the BRCA2 gene. This sequence change replaces arginine with histidine at codon 2336 of the BRCA2 protein (p.Arg2336His). RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer, Fanconi anemia, and acute myeloid leukemia (PMID: 22486713, 25395318, 12065746, 16115142, 26968956, 22430266). This variant is also known as 7235G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38077) with 26 submissions, all of which describe it as pathogenic, 3 stars, reviewed by expert panel. In silico predictions show this variant to pathogenic (PMID: 27124784). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16792514, 22505045, 20215541). Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9150172, 22399190, 20960228, 21548014, 17576681, 9536098, 22505045). Therefore, this variant has been classified as Pathogenic. (less)
Sex: female
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Pathogenic
(Sep 16, 2021)
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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: SCV000296656.5
First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024 |
Comment:
In the published literature, in vitro functional studies have shown that this variant has a deleterious effect on BRCA2 mRNA splicing and causes the synthesis … (more)
In the published literature, in vitro functional studies have shown that this variant has a deleterious effect on BRCA2 mRNA splicing and causes the synthesis of BRCA2 mRNA without exons 12 and/or 13 (PMIDs: 22505045 (2012), 16792514 (2006)). This variant has also been reported in affected individuals with breast and/or ovarian cancer as well as Fanconi anemia (PMIDs: 30825404 (2019), 25395318 (2014), 18489799 (2008), 12065746 (2002)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Oct 25, 2012)
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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: SCV000054266.6
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Pathogenic
(Jul 26, 2002)
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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: SCV000030144.4
First in ClinVar: Apr 04, 2013 Last updated: May 21, 2018 |
Comment on evidence:
In the Fanconi anemia (FANCD1; 605724) cell line EUFA579, Howlett et al. (2002) identified a G-to-A transition at nucleotide 7235 in exon 13 on 1 … (more)
In the Fanconi anemia (FANCD1; 605724) cell line EUFA579, Howlett et al. (2002) identified a G-to-A transition at nucleotide 7235 in exon 13 on 1 allele of the BRCA2 gene, and a 5837TC to AG mutation on the other allele (600185.0021). (less)
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Pathogenic
(Jun 11, 2019)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV001451880.1
First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020 |
Number of individuals with the variant: 2
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(Feb 20, 2004)
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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
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146991.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian Non Hispanic
Observation 4:
Number of individuals with the variant: 2
Ethnicity/Population group: Central/Eastern European
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Italian
Observation 6:
Number of individuals with the variant: 10
Ethnicity/Population group: Western European
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, French Canadian
Observation 8:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Italian
Observation 9:
Number of individuals with the variant: 1
Ethnicity/Population group: Western Europeanan, Central/Eastern European
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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: SCV000587878.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(Feb 10, 2014)
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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: SCV000863733.1 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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not provided
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: SCV000592088.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Arg2336His variant has been previously reported in the literature and by our laboratory. It has been reported in the literature in 7 out of … (more)
The p.Arg2336His variant has been previously reported in the literature and by our laboratory. It has been reported in the literature in 7 out of 12688 proband chromosomes (Barber 2005, Easton 2007, Machackova 2008, Sanz 2010) in individuals with hereditary breast cancer, male breast cancer and AML. It has also been reported by our laboratory in one individual who met criteria for hereditary breast and ovarian cancer testing. The p.Arg2336His variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. It is listed in dbSNP database (ID#: rs28897743), but no frequency information was provided. This variant was shown to induce aberrant splicing resulting in the deletion of the 70-bp exon 13 from the mRNA and causes a frameshift and premature stop codon in exon 14 (Thomassen 2006). Mutations causing frameshift and truncation of the BRCA2 protein have been shown to be clinically important, and loss of function of the BRCA2 gene represents an established disease mechanism in hereditary breast cancer patients. In addition, functional assays have shown a reduction in the full-length transcript production compared with wild-type cells, hypersensitivity to various DNA damaging agents, defect in HR-mediated DNA repair and an increase in genomic instability has been reported (Biswas 2011, Farrugia 2008). In summary, based on the above information, this variant is classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951528.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV000733290.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Likely pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
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Fanconi anemia complementation group D1
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133114.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
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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: SCV002588906.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Fanconi anemia complementation group D1
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927872.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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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 |
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Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. | De Talhouet S | Scientific reports | 2020 | PMID: 32341426 |
Identification of a novel germline BRCA2 variant in a Chinese breast cancer family. | Cheng J | Journal of cellular and molecular medicine | 2020 | PMID: 31782247 |
Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals. | Shao D | Cancer science | 2020 | PMID: 31742824 |
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
Prevalence, spectrum, and founder effect of BRCA1 and BRCA2 mutations in epithelial ovarian cancer from the Middle East. | Siraj AK | Human mutation | 2019 | PMID: 30825404 |
Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. | Abou Tayoun AN | Human mutation | 2018 | PMID: 30192042 |
BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. | Li A | Gynecologic oncology | 2018 | PMID: 30078507 |
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 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? | Alemar B | PloS one | 2017 | PMID: 29161300 |
The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next-generation sequencing. | Lang GT | International journal of cancer | 2017 | PMID: 28294317 |
Comparative analysis of BRCA1 and BRCA2 variants of uncertain significance in patients with breast cancer: a multifactorial probability-based model versus ACMG standards and guidelines for interpreting sequence variants. | Park KS | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 27124784 |
Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. | Ghazwani Y | Cancer genetics | 2016 | PMID: 26968956 |
Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases. | Vail PJ | Journal of community genetics | 2015 | PMID: 25782689 |
Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer. | Trujillano D | The Journal of molecular diagnostics : JMD | 2015 | PMID: 25556971 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry. | Peixoto A | Clinical genetics | 2015 | PMID: 24916970 |
Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14. | Coppa A | Breast cancer research and treatment | 2014 | PMID: 25395318 |
Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene. | Degrolard-Courcet E | European journal of human genetics : EJHG | 2014 | PMID: 24301060 |
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. | Karami F | BioMed research international | 2013 | PMID: 24312913 |
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. | Houdayer C | Human mutation | 2012 | PMID: 22505045 |
Detection of BRCA1/2 mutations in breast cancer patients from Thailand and Pakistan. | Ahmad J | Clinical genetics | 2012 | PMID: 22486713 |
Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. | Finkelman BS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22430266 |
Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel. | Laitman Y | Breast cancer research and treatment | 2012 | PMID: 22399190 |
The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations. | Myers K | Pediatric blood & cancer | 2012 | PMID: 21548014 |
A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. | Biswas K | Blood | 2011 | PMID: 21719596 |
Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. | Laitman Y | Breast cancer research and treatment | 2011 | PMID: 20960228 |
Breast and ovarian cancer risk evaluation in families with a disease-causing mutation in BRCA1/2. | Beristain E | Journal of community genetics | 2010 | PMID: 22460208 |
A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. | Sanz DJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2010 | PMID: 20215541 |
Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. | Machackova E | BMC cancer | 2008 | PMID: 18489799 |
Functional assays for classification of BRCA2 variants of uncertain significance. | Farrugia DJ | Cancer research | 2008 | PMID: 18451181 |
Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients. | Konstantopoulou I | Breast cancer research and treatment | 2008 | PMID: 17453335 |
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Childhood cancer in families with and without BRCA1 or BRCA2 mutations ascertained at a high-risk breast cancer clinic. | Brooks GA | Cancer biology & therapy | 2006 | PMID: 16931905 |
A missense mutation in exon 13 in BRCA2, c.7235G>A, results in skipping of exon 13. | Thomassen M | Genetic testing | 2006 | PMID: 16792514 |
Inherited FANCD1/BRCA2 exon 7 splice mutations associated with acute myeloid leukaemia in Fanconi anaemia D1 are not found in sporadic childhood leukaemia. | Barber LM | British journal of haematology | 2005 | PMID: 16115142 |
A high proportion of founder BRCA1 mutations in Polish breast cancer families. | Górski B | International journal of cancer | 2004 | PMID: 15146557 |
BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. | Claes K | British journal of cancer | 2004 | PMID: 15026808 |
Biallelic inactivation of BRCA2 in Fanconi anemia. | Howlett NG | Science (New York, N.Y.) | 2002 | PMID: 12065746 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
BRCA2 mutations in hereditary breast and ovarian cancer in France. | Serova-Sinilnikova OM | American journal of human genetics | 1997 | PMID: 9150172 |
[The value of fetal blood flow measurements in intrauterine growth retardation in comparison with E3 and human placental lactogen determinations]. | Spernol R | Geburtshilfe und Frauenheilkunde | 1989 | PMID: 2661312 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 | - | - | - | - |
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Text-mined citations for rs28897743 ...
HelpRecord last updated Jun 02, 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.