Submissions for variant NM_000059.4(BRCA2):c.1343G>A (p.Arg448His)

gnomAD frequency: 0.00001  dbSNP: rs80358423

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130010	SCV000184835	likely benign	Hereditary cancer-predisposing syndrome	2018-02-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000587298	SCV000569844	uncertain significance	not provided	2021-06-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1571G>A; Observed in individuals with breast or ovarian cancer, but also in healthy controls (Claes 2004, Momozawa 2018, Peixoto 2020); This variant is associated with the following publications: (PMID: 30287823, 15026808, 18403564, 27535533, 31131967, 32850417)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175372	SCV000694533	uncertain significance	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1343G>A (p.Arg448His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 295704 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1343G>A has been reported in the literature in a family affected with breast cancer (Claes_2004). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Another study (Momozawa_2018) did not detect the variant in any of the breast cancer patients analyzed but detected it at a frequency of 0.00013 in controls who were 60 years old or over and did not have past history nor family history of cancers. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.2934T>G, p.Tyr978X; BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000112910	SCV000785485	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-08-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130010	SCV000911449	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 448 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one suspected hereditary breast and ovarian cancer family (PMID: 15026808) and in a prostate cancer case-control study in 2/7636 cases and 3/12366 unaffected individuals (PMID: 31214711). This variant also has been reported in breast and pancreatic cancer case-control studies in which this variant was detected only in unaffected individuals and was absent in cancer cases (PMID: 30287823, 32980694, 33471991). This variant has been identified in 1/248242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587298	SCV001133676	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/248242 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with a personal and/or family history of breast cancer (PMIDs: 15026808 (2004), 31853058 (2020), 35753294 (2022)) and prostate cancer (PMID: 31214711 (2020)). The variant has also been reported in healthy individuals (PMIDs: 30287823 (2018), 30630528 (2019), 31214711 (2020), 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000112910	SCV001138996	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001495330	SCV001700010	likely benign	Hereditary breast ovarian cancer syndrome	2025-02-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130010	SCV003850016	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000112910	SCV004846906	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 448 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one suspected hereditary breast and ovarian cancer family (PMID: 15026808) and in a prostate cancer case-control study in 2/7636 cases and 3/12366 unaffected individuals (PMID: 31214711). This variant also has been reported in breast and pancreatic cancer case-control studies in which this variant was detected only in unaffected individuals and was absent in cancer cases (PMID: 30287823, 32980694, 33471991). This variant has been identified in 1/248242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112910	SCV000145856	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587298	SCV001979611	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587298	SCV001980546	likely benign	not provided		no assertion criteria provided	clinical testing