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

gnomAD frequency: 0.00001  dbSNP: rs80358624

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	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: 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).
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.