Variant allele predicted to encode a truncated non-functional protein.
ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.2224C>T (p.Gln742Ter)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2016 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.2224C>T (p.Gln742Ter)
Variation ID: 51257 Accession: VCV000051257.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32336579 (GRCh38) [ NCBI UCSC ] 13: 32910716 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 8, 2024 Sep 8, 2016 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000059.4:c.2224C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Gln742Ter nonsense NC_000013.11:g.32336579C>T NC_000013.10:g.32910716C>T NG_012772.3:g.26100C>T LRG_293:g.26100C>T LRG_293t1:c.2224C>T LRG_293p1:p.Gln742Ter U43746.1:n.2452C>T - Protein change
- Q742*
- Other names
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p.Q742*:CAA>TAA
2452C>T
- Canonical SPDI
- NC_000013.11:32336578:C: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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Exome Aggregation Consortium (ExAC) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
18962 | 19121 | |
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. |
|---|---|---|---|---|
| Pathogenic (6) |
reviewed by expert panel
|
Sep 8, 2016 | RCV000077273.18 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2024 | RCV000212220.19 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 24, 2023 | RCV000496760.16 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 17, 2023 | RCV000568409.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2022 | RCV002490602.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 19, 2023 | RCV003473311.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 11, 2024 | RCV004732603.1 |
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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|---|---|---|---|---|---|
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Pathogenic
(Sep 08, 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: SCV000300498.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
|
|
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Pathogenic
(Sep 25, 2019)
|
criteria provided, single submitter
Method: research
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI GT
Accession: SCV001190320.1 First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016 |
Number of individuals with the variant: 1
|
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Pathogenic
(Apr 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002800810.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Feb 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004210391.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Jul 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296604.4
First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000029 (1/34534 chromosomes, http://gnomad.broadinstitute.org), is … (more)
This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000029 (1/34534 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer in the published literature (PMID: 30630528 (2019), 29446198 (2018), 26681312 (2015), 26543556 (2015), 25628955 (2015), 16030099 (2005)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(Feb 07, 2022)
|
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: SCV000916834.2
First in ClinVar: Jun 02, 2019 Last updated: Mar 12, 2022 |
Comment:
Variant summary: BRCA2 c.2224C>T (p.Gln742X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA2 c.2224C>T (p.Gln742X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251260 control chromosomes. c.2224C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, who were mostly of Hispanic origin (examples: Weitzel 2005, Lee 2008, Nahleh 2015, Dean 2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified 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: SCV000326673.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Dec 24, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001586459.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln742*) 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.Gln742*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 16030099, 18284688, 25628955, 26543556, 26681312). ClinVar contains an entry for this variant (Variation ID: 51257). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Feb 17, 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: SCV001355741.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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
(Jul 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004847023.1
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)
|
Comment:
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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)
Number of individuals with the variant: 3
|
|
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Pathogenic
(Sep 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000661152.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.Q742* pathogenic mutation (also known as c.2224C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at … (more)
The p.Q742* pathogenic mutation (also known as c.2224C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2224. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation has been observed in multiple Mexican probands with personal and/or family histories of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71; Lee E et al. Breast Cancer Res, 2008 Feb;10:R19; Villarreal-Garza C et al, 2015 Apr;150:389-94; Dean M et al. Gigascience, 2015 Nov;4:50; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Cruz-Correa M et al. Hered Cancer Clin Pract, 2017 Jan;15:3; Fernández-Lopez JC et al. Hum Genomics, 2019 01;13:3). This mutation was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 2452C>T in 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 interpreted as a disease-causing mutation. (less)
|
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Pathogenic
(Mar 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210456.13
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2452C>T; This variant is associated with the following publications: (PMID: 28127413, 18284688, 30630528, 34413315, 25525159, 16030099, 26295337, 25716084, 25628955, 27221827, 29446198, 26543556, 29922827, 25371446, 35875314, 31853058, 33293522) (less)
|
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Pathogenic
(May 29, 2002)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146017.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean, Western European
|
|
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Pathogenic
(Mar 11, 2024)
|
no assertion criteria provided
Method: clinical testing
|
BRCA2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805668.2
First in ClinVar: Jun 03, 2016 Last updated: Oct 08, 2024 |
Comment:
The BRCA2 c.2224C>T variant is predicted to result in premature protein termination (p.Gln742*). This variant has been reported in patients with breast and/or ovarian cancer … (more)
The BRCA2 c.2224C>T variant is predicted to result in premature protein termination (p.Gln742*). This variant has been reported in patients with breast and/or ovarian cancer (Weitzel et al. 2005. PubMed ID: 16030099; Dean et al. 2015. PubMed ID: 26543556; Rebbeck et al. 2018. PubMed ID: 29446198; Fernández-Lopez et al. 2019. PubMed ID: 30630528). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51257). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
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Pathogenic
(Feb 26, 2013)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000109070.3
First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014 |
|
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Pathogenic
(Jan 31, 2014)
|
no assertion criteria provided
Method: research
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587625.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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Comment:
Comment:
This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000029 (1/34534 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer in the published literature (PMID: 30630528 (2019), 29446198 (2018), 26681312 (2015), 26543556 (2015), 25628955 (2015), 16030099 (2005)). Based on the available information, this variant is classified as pathogenic.
Comment:
Variant summary: BRCA2 c.2224C>T (p.Gln742X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251260 control chromosomes. c.2224C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, who were mostly of Hispanic origin (examples: Weitzel 2005, Lee 2008, Nahleh 2015, Dean 2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Gln742*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 16030099, 18284688, 25628955, 26543556, 26681312). ClinVar contains an entry for this variant (Variation ID: 51257). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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.
Comment:
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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.
Comment:
The p.Q742* pathogenic mutation (also known as c.2224C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2224. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation has been observed in multiple Mexican probands with personal and/or family histories of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71; Lee E et al. Breast Cancer Res, 2008 Feb;10:R19; Villarreal-Garza C et al, 2015 Apr;150:389-94; Dean M et al. Gigascience, 2015 Nov;4:50; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Cruz-Correa M et al. Hered Cancer Clin Pract, 2017 Jan;15:3; Fernández-Lopez JC et al. Hum Genomics, 2019 01;13:3). This mutation was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 2452C>T in 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 interpreted as a disease-causing mutation.
Comment:
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2452C>T; This variant is associated with the following publications: (PMID: 28127413, 18284688, 30630528, 34413315, 25525159, 16030099, 26295337, 25716084, 25628955, 27221827, 29446198, 26543556, 29922827, 25371446, 35875314, 31853058, 33293522)
Comment:
The BRCA2 c.2224C>T variant is predicted to result in premature protein termination (p.Gln742*). This variant has been reported in patients with breast and/or ovarian cancer (Weitzel et al. 2005. PubMed ID: 16030099; Dean et al. 2015. PubMed ID: 26543556; Rebbeck et al. 2018. PubMed ID: 29446198; Fernández-Lopez et al. 2019. PubMed ID: 30630528). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51257). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
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. |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
Comment:
This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000029 (1/34534 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer in the published literature (PMID: 30630528 (2019), 29446198 (2018), 26681312 (2015), 26543556 (2015), 25628955 (2015), 16030099 (2005)). Based on the available information, this variant is classified as pathogenic.
Comment:
Variant summary: BRCA2 c.2224C>T (p.Gln742X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251260 control chromosomes. c.2224C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, who were mostly of Hispanic origin (examples: Weitzel 2005, Lee 2008, Nahleh 2015, Dean 2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Gln742*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 16030099, 18284688, 25628955, 26543556, 26681312). ClinVar contains an entry for this variant (Variation ID: 51257). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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.
Comment:
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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.
Comment:
The p.Q742* pathogenic mutation (also known as c.2224C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2224. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation has been observed in multiple Mexican probands with personal and/or family histories of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71; Lee E et al. Breast Cancer Res, 2008 Feb;10:R19; Villarreal-Garza C et al, 2015 Apr;150:389-94; Dean M et al. Gigascience, 2015 Nov;4:50; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Cruz-Correa M et al. Hered Cancer Clin Pract, 2017 Jan;15:3; Fernández-Lopez JC et al. Hum Genomics, 2019 01;13:3). This mutation was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 2452C>T in 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 interpreted as a disease-causing mutation.
Comment:
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2452C>T; This variant is associated with the following publications: (PMID: 28127413, 18284688, 30630528, 34413315, 25525159, 16030099, 26295337, 25716084, 25628955, 27221827, 29446198, 26543556, 29922827, 25371446, 35875314, 31853058, 33293522)
Comment:
The BRCA2 c.2224C>T variant is predicted to result in premature protein termination (p.Gln742*). This variant has been reported in patients with breast and/or ovarian cancer (Weitzel et al. 2005. PubMed ID: 16030099; Dean et al. 2015. PubMed ID: 26543556; Rebbeck et al. 2018. PubMed ID: 29446198; Fernández-Lopez et al. 2019. PubMed ID: 30630528). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51257). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Influence of germline BRCA genotype on the survival of patients with triple-negative breast cancer. | Villarreal-Garza C | Cancer research communications | 2021 | PMID: 35875314 |
| 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 |
| Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
| Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines. | Cruz-Correa M | Hereditary cancer in clinical practice | 2017 | PMID: 28127413 |
| 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 |
| Addressing health disparities in Hispanic breast cancer: accurate and inexpensive sequencing of BRCA1 and BRCA2. | Dean M | GigaScience | 2015 | PMID: 26543556 |
| Development and Validation of a Next-Generation Sequencing Assay for BRCA1 and BRCA2 Variants for the Clinical Laboratory. | Strom CM | PloS one | 2015 | PMID: 26295337 |
| The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer. | Villarreal-Garza C | Breast cancer research and treatment | 2015 | PMID: 25716084 |
| Clinical and pathological characteristics of Hispanic BRCA-associated breast cancers in the American-Mexican border city of El Paso, TX. | Nahleh Z | American journal of cancer research | 2014 | PMID: 25628955 |
| BRCA1 germline mutations may be associated with reduced ovarian reserve. | Wang ET | Fertility and sterility | 2014 | PMID: 25256924 |
| 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 |
| Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. | Lee E | Breast cancer research : BCR | 2008 | PMID: 18284688 |
| Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. | Weitzel JN | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2005 | PMID: 16030099 |
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Text-mined citations for rs80358494 ...
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Record last updated Oct 27, 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.