ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3814A>G (p.Met1272Val)

gnomAD frequency: 0.00001  dbSNP: rs80358624
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000203673 SCV000072284 likely benign Hereditary breast ovarian cancer syndrome 2023-12-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130732 SCV000185623 likely benign Hereditary cancer-predisposing syndrome 2018-03-20 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 RCV001703944 SCV000210596 likely benign not provided 2018-12-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17100994, 28263838, 21520273, 14973102, 20104584, 16949048, 24817641, 30287823, 31825140)
Counsyl RCV000083100 SCV000489068 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2016-08-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044271 SCV000694720 likely benign not specified 2023-12-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3814A>G (p.Met1272Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-06 in 226788 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3814A>G has been reported in the literature individuals affected with and/or undergoing multigene panel testing for Breast Cancer and also in unaffected controls (e.g. Suter_2004, Kim_2006, Han_2006, Borg_2010, Zanella_2017, Momozawa_2018, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 21520273, 17100994, 16949048, 30287823, 14973102, 28263838, 33471991). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as benign/likely benign and two classified it as uncertain significance. Based on the emerging majority consensus and the lack of concrete actionable evidence as outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV000130732 SCV000910980 benign Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing
Mendelics RCV000083100 SCV001139073 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001703944 SCV002047251 uncertain significance not provided 2023-02-10 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.0000089 (2/225816 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMIDs: 14973102 (2004), 16949048 (2006), 17100994 (2006), 20104584 (2010), 30287823 (2018)) and prostate cancer (PMID: 31214711 (2020)). 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington RCV000130732 SCV003846891 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 RCV000083100 SCV004845228 benign Breast-ovarian cancer, familial, susceptibility to, 2 2023-10-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083100 SCV000115174 benign Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083100 SCV000146302 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353829 SCV000591876 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Met1272Val variant was identified in 4 of 7082 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast cancer and was not identified in 653 control chromosomes from healthy individuals (Borg 2010, Capanu 2011, Han 2006, Suter 2004). The variant was also identified in dbSNP (ID: rs80358624) “With other allele”; in the Exome Variant Server project in 1 of 8585 European American alleles; the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 of 56282 chromosomes (frequency: 0.00001777) from a population of European (Non-Finnish) individuals, and 1 of 10174 chromosomes from a Latino population, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also found in HGMD (1X as “unknown”), the BIC database (3X with unknown clinical importance), UMD (2X as an unknown variant) and the ClinVar database 4 times with conflicting classifications (1X as benign from the sharing clinical reports project, 1X as likely benign by GeneDx and 2X as uncertain significance (Ambry and BIC)). The p.Met1272 residue is not conserved in mammals and the variant amino acid Valine (Val) is present in rat and chickens increasing the likelihood that this variant does not have clinical significance. In addition, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Of note, 4 out of 5 in-silico splicing software predict the creation of a 3' splice site, but the effect of this variant on splicing cannot be determined without further evaluation. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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