Submissions for variant NM_000059.4(BRCA2):c.1600G>A (p.Glu534Lys)

gnomAD frequency: 0.00001  dbSNP: rs276174810

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131321	SCV000186294	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-15	criteria provided, single submitter	clinical testing	The p.E534K variant (also known as c.1600G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1600. The glutamic acid at codon 534 is replaced by lysine, an amino acid with similar properties. This alteration was observed in a series of 187 Malaysian women with breast cancer who were diagnosed under age 40 or had strong family history of breast or ovarian cancer (Thirthagiri E etal. Breast Cancer Res. 2008;10:R5 9). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000215004	SCV000279592	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: ability to rescue cell lethality and exhibited no sensitivity to DNA damaging agents in a mouse embryonic stem cell (mESC)-based assay (PMID: 33314489); 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 1828G>A; This variant is associated with the following publications: (PMID: 18627636, 33471991, 32377563, 29884841, 31853058, 32467295, 33314489)
Color Diagnostics, LLC DBA Color Health	RCV000131321	SCV000688713	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 534 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). A functional study has shown this variant does not impact cell viability or sensitivity to DNA-damaging agents (PMID: 33314489). This variant has been reported in at least two individuals affected with breast cancer and two unaffected individuals (PMID: 18627636, 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007646). This variant has been identified in 4/248706 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.
Counsyl	RCV000031330	SCV000785626	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-10-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001327852	SCV001518944	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000215004	SCV002774510	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131321	SCV003851517	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317049	SCV004021053	uncertain significance	not specified	2023-06-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1600G>A (p.Glu534Lys) 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 3.7e-05 in 271478 control chromosomes (gnomAD, Dong_2021). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.1600G>A has been reported in the literature in individuals affected withbreast cancer without any evidence for causality (Thirthagiri_2008, Dorling_2021, Sullivan_2021), therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication using Brca2 deficient mouse embryonic stem cells showed no damaging effects of this variant: the variant could rescue cell viability and was not sensative to DNA damaging agents (Sullivan_2021). The following publications have been ascertained in the context of this evaluation (PMID: 32467295, 33314489, 18627636, 33471991). Seven ClinVar submitters have assessed this variant since 2014: six classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004803003	SCV004846939	uncertain significance	BRCA2-related cancer predisposition	2024-06-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 534 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). A functional study has shown this variant does not impact cell viability or sensitivity to DNA-damaging agents (PMID: 33314489). This variant has been reported in at least two individuals affected with breast cancer and two unaffected individuals (PMID: 18627636, 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007646). This variant has been identified in 4/248706 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.
Sharing Clinical Reports Project (SCRP)	RCV000031330	SCV000053935	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-07-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031330	SCV000145896	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing