Submissions for variant NM_000059.4(BRCA2):c.8771A>G (p.Glu2924Gly)

dbSNP: rs876658844

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213436	SCV000274620	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-14	criteria provided, single submitter	clinical testing	The p.E2924G variant (also known as c.8771A>G), located in coding exon 21 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8771. The glutamic acid at codon 2924 is replaced by glycine, an amino acid with similar properties. In one study, this variant was observed in 1/1001 patients with non-mucinous ovarian carcinoma and classified as a variant of uncertain significance by the authors (Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690114	SCV000817792	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-06-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with glycine at codon 2924 of the BRCA2 protein (p.Glu2924Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with ovarian cancer (PMID: 22711857). ClinVar contains an entry for this variant (Variation ID: 230922). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778806	SCV002014802	uncertain significance	not specified	2021-10-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8771A>G (p.Glu2924Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250670 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8771A>G has been reported in at least one individual affected with nonmucinous ovarian carcinoma without strong evidence for causality (Alsop_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002286723	SCV002577078	uncertain significance	not provided	2022-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with ovarian cancer (Alsop 2012); Also known as 8999A>G; This variant is associated with the following publications: (PMID: 12228710, 22711857)
All of Us Research Program, National Institutes of Health	RCV003997870	SCV004826691	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2924 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 ovarian cancer (PMID: 22711857) and in an individual with a personal or family history of breast cancer (PMID: 35980532). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV002286723	SCV005197326	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing