Submissions for variant NM_000059.4(BRCA2):c.172G>A (p.Glu58Lys)

gnomAD frequency: 0.00002  dbSNP: rs397507603

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195636	SCV000254171	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 58 of the BRCA2 protein (p.Glu58Lys). This variant is present in population databases (rs397507603, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 26287763). This variant is also known as c.400G>A. ClinVar contains an entry for this variant (Variation ID: 91755). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000216277	SCV000274011	likely benign	Hereditary cancer-predisposing syndrome	2021-08-09	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.
Counsyl	RCV000077663	SCV000488840	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216277	SCV000683440	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 58 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 individual each affected with breast cancer and prostate cancer and in an unaffected individual (PMID: 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_007230). This variant has been identified in 7/251326 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	RCV000985468	SCV001133690	uncertain significance	not provided	2020-11-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000077663	SCV001138946	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824599	SCV002074414	uncertain significance	not specified	2022-01-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.172G>A (p.Glu58Lys) results in a 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 2.8e-05 in 251326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.172G>A has been reported in the literature as a VUS suspected to be benign in a study of women with breast cancer (example, Pal_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000077663	SCV004846740	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 58 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 individual each affected with breast cancer and prostate cancer and in an unaffected individual (PMID: 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_007230). This variant has been identified in 7/251326 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.
Baylor Genetics	RCV004566942	SCV005059090	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077663	SCV000109466	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-24	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077663	SCV004228386	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)