Submissions for variant NM_000059.4(BRCA2):c.8541A>C (p.Glu2847Asp)

dbSNP: rs1555287759

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580837	SCV000683981	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 2847 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. 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	RCV000781049	SCV000918829	uncertain significance	not specified	2018-02-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8541A>C (p.Glu2847Asp) results in a conservative amino acid change located in the Tower domain (IPR015205) of 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 121324 control chromosomes in ExAC. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8541A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002529093	SCV003261405	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2847 of the BRCA2 protein (p.Glu2847Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 489791). 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.
All of Us Research Program, National Institutes of Health	RCV004001246	SCV004846038	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580837	SCV005551980	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-12	criteria provided, single submitter	clinical testing	The p.E2847D variant (also known as c.8541A>C), located in coding exon 19 of the BRCA2 gene, results from an A to C substitution at nucleotide position 8541. The glutamic acid at codon 2847 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.