Submissions for variant NM_000059.4(BRCA2):c.7418G>A (p.Cys2473Tyr)

gnomAD frequency: 0.00002  dbSNP: rs55924966

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132080	SCV000187144	likely benign	Hereditary cancer-predisposing syndrome	2018-04-30	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.
Color Diagnostics, LLC DBA Color Health	RCV000132080	SCV000906935	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 2473 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 an individual affected with breast cancer (PMID: 29854292). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192570	SCV001360797	uncertain significance	not specified	2019-06-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7418G>A (p.Cys2473Tyr) 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 was absent in 250980 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2837A>G has been reported in the literature in an individual affected with breast cancer, however without strong evidence for causality (Encinas_2018). Co-occurrences with another pathogenic BRCA2 variant have been reported (c.5454delA (p.Cys1820AlafsX20) in an internal sample and in the NHGRI BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as likely benign (1x) or VUS (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284106	SCV001469712	uncertain significance	not provided	2019-11-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001462591	SCV001666511	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001284106	SCV001814966	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Observed in a woman with breast cancer diagnosed under age 35 who also carried a second BRCA2 missense variant (Encinas et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7646G>A; This variant is associated with the following publications: (PMID: 29884841, 32377563, 29854292, 31191615)
All of Us Research Program, National Institutes of Health	RCV004803895	SCV005425747	uncertain significance	BRCA2-related cancer predisposition	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 2473 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 an individual affected with breast cancer (PMID: 29854292). This variant has not been identified 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)	RCV000113753	SCV000147078	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing