ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7964A>G (p.Gln2655Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.7964A>G (p.Gln2655Arg)
Variation ID: 52450 Accession: VCV000052450.32
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q13.1 13: 32362681 (GRCh38) [ NCBI UCSC ] 13: 32936818 (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 13, 2024 Sep 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000059.4:c.7964A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Gln2655Arg missense NC_000013.11:g.32362681A>G NC_000013.10:g.32936818A>G NG_012772.3:g.52202A>G LRG_293:g.52202A>G LRG_293t1:c.7964A>G LRG_293p1:p.Gln2655Arg U43746.1:n.8192A>G - Protein change
- Q2655R
- Other names
- p.Q2655R:CAA>CGA
- p.Gln2655Arg
- Canonical SPDI
- NC_000013.11:32362680:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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. |
|||
BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
- | - |
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. |
---|---|---|---|---|
Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000113846.10 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 25, 2024 | RCV000212265.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2023 | RCV000510118.11 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 27, 2023 | RCV001378206.6 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 22, 2024 | RCV003460615.3 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139196.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Likely pathogenic
(Aug 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428744.2
First in ClinVar: Aug 16, 2020 Last updated: Sep 25, 2021 |
|
|
Likely pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
unknown
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV005045707.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
The c.7964A>G variant in the BRCA2 gene is located in exon 17, and replaces glutamine with arginine at codon 2655 (p.Gln2655Arg) in the BRCA2 protein. … (more)
The c.7964A>G variant in the BRCA2 gene is located in exon 17, and replaces glutamine with arginine at codon 2655 (p.Gln2655Arg) in the BRCA2 protein. This variant has been reported in individuals affected with breast cancer (PMID: 33471991) and in an individual affected with Fanconi Anemia (PMID: 20608899). Experimental studies have shown that this variant has a deleterious effect in a homology directed DNA repair (HDR) assay (PMID: 29394989, 29884841). ClinVar contains an entry for this variant (ID: 52450). This variant is absent in the general population according to gnomAD. In silico prediction algorithms suggest that this variant may have deleterious impact on protein structure and function. Therefore, the c.7964A>G (p.Gln2655Arg) variant in the BRCA2 gene is classified as likely pathogenic. (less)
|
|
Likely pathogenic
(Sep 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210453.14
First in ClinVar: Feb 24, 2015 Last updated: Oct 08, 2024 |
Comment:
Observed in individuals undergoing multi-gene panel testing based on a personal and/or family history of cancer, as well as in individuals with breast cancer in … (more)
Observed in individuals undergoing multi-gene panel testing based on a personal and/or family history of cancer, as well as in individuals with breast cancer in a case-control study (PMID: 31853058, 33471991); Published functional studies demonstrate decreased homology directed repair activity (PMID: 29394989, 29884841, 35665744); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.8192A>G; This variant is associated with the following publications: (PMID: 19043619, 26064523, 11430722, 29394989, 29884841, 35665744, 31131967, 29158857, 31853058, 32377563, 33471991, 20608899, 12228710, 36721989) (less)
|
|
Likely pathogenic
(Aug 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004698108.2
First in ClinVar: Mar 10, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS3,PM3,PM2_SUP
Clinical Features:
Family history of cancer (present)
Sex: female
|
|
Likely pathogenic
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216053.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Likely pathogenic
(May 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022082.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Likely pathogenic
(Dec 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001575727.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2655 of the BRCA2 protein (p.Gln2655Arg). … (more)
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2655 of the BRCA2 protein (p.Gln2655Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 20608899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This missense change has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 52450). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (Invitae). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 29884841). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
Pathogenic
(Mar 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000608034.6
First in ClinVar: Oct 23, 2017 Last updated: May 01, 2024 |
Comment:
The p.Q2655R pathogenic mutation (also known as c.7964A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at … (more)
The p.Q2655R pathogenic mutation (also known as c.7964A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7964. The glutamine at codon 2655 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in trans with a BRCA2 pathogenic nonsense mutation in an archived medulloblastoma sample from a deceased girl with Fanconi Anemia (Ruud E et al. Acta Paediatr. 2001 May;90:580-3; Bodd TL et al. Acta Paediatr. 2010 Nov;99:1741-3). This alteration is also defective in a homology directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet. 2018 02;102(2):233-248). Based on internal structural analysis this alteration is likely to disrupt DSS1 binding and is predicted to be as destabilizing to the local structure as other known pathogenic variants (Yang H et al. Science 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, 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)
|
|
Pathogenic
(Feb 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046101.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
This variant has been reported with another pathogenic BRCA2 variant in trans (on a different chromosome) in an individual affected with Fanconi Anemia (PMIDs: 11430722 … (more)
This variant has been reported with another pathogenic BRCA2 variant in trans (on a different chromosome) in an individual affected with Fanconi Anemia (PMIDs: 11430722 (2001) and 20608899 (2010)). In addition, this variant was reported to have a damaging effect on homology-directed repair in a peer-reviewed experimental study (PMID: 29394989 (2018)). This variant has not been reported in large, multi-ethnic general populations. Variant is predicted to have a damaging effect on the protein and is located in a potentially critical domain of the protein. Based on the available information, this variant is classified as pathogenic. (less)
|
|
Likely pathogenic
(Dec 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226654.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PM2, PS2, PS3_moderate
Number of individuals with the variant: 2
|
|
Likely pathogenic
(Mar 29, 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: SCV000911874.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in a homology-mediated repair assay (PMID: 29394989). This variant has been detected in two individuals affected with breast cancer and absent in 53461 unaffected individuals in a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000247). This variant also has been found in trans with a pathogenic truncation variant in BRCA2 in an individual diagnosed with Fanconi anemia (PMID: 20608899). 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 Likely Pathogenic. (less)
|
|
Likely Pathogenic
(Jan 10, 2024)
|
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: SCV004845578.1
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 missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in a homology-mediated repair assay (PMID: 29394989). This variant has been detected in two individuals affected with breast cancer and absent in 53461 unaffected individuals in a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000247). This variant also has been found in trans with a pathogenic truncation variant in BRCA2 in an individual diagnosed with Fanconi anemia (PMID: 20608899). 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 Likely Pathogenic. (less)
Number of individuals with the variant: 2
|
|
Uncertain significance
(Sep 06, 2017)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785547.2
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
|
|
Uncertain significance
(Dec 23, 2003)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147229.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
|
|
click to load more click to collapse | |||||
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
---|---|---|---|---|
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 |
Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. | Guidugli L | American journal of human genetics | 2018 | PMID: 29394989 |
Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup. | Miele E | Biomarker research | 2015 | PMID: 26064523 |
An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex. | Doss CG | Cell biochemistry and biophysics | 2014 | PMID: 24817641 |
Fanconi anaemia, BRCA2 and familial considerations - follow up on a previous case report. | Bodd TL | Acta paediatrica (Oslo, Norway : 1992) | 2010 | PMID: 20608899 |
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. | Karchin R | Cancer informatics | 2008 | PMID: 19043619 |
BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. | Yang H | Science (New York, N.Y.) | 2002 | PMID: 12228710 |
Microcephalus, medulloblastoma and excessive toxicity from chemotherapy: an unusual presentation of Fanconi anaemia. | Ruud E | Acta paediatrica (Oslo, Norway : 1992) | 2001 | PMID: 11430722 |
Text-mined citations for rs80359024 ...
HelpRecord last updated Oct 13, 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.