Submissions for variant NM_000059.4(BRCA2):c.8539G>A (p.Glu2847Lys)

gnomAD frequency: 0.00001  dbSNP: rs80359108

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045551	SCV000073564	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-13	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 2847 of the BRCA2 protein (p.Glu2847Lys). This variant is present in population databases (rs80359108, gnomAD 0.003%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 52616). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 37922907). 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.
GeneDx	RCV000767049	SCV000565868	uncertain significance	not provided	2024-12-30	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8767G>A; This variant is associated with the following publications: (PMID: 19043619, 29394989, 29884841, 35665744, 37922907, 12228710)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479458	SCV000600812	uncertain significance	not specified	2016-12-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564844	SCV000665393	likely benign	Hereditary cancer-predisposing syndrome	2020-03-04	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	RCV000564844	SCV000683980	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2847 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported conflicting findings on variant protein function in homology-directed repair assay from loss-of-function to intermediate activities (PMID: 29394989, 29884841). Further, this variant increased sensitivity to PARP inhibitors and decreased cell viability in mouse embryonic stem cells (PMID: 37922907). This variant has been reported in an individual affected with uterine corpus endometrial carcinoma (PMID: 26689913) and also detected in an individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/13-32945144-G-A). This variant has been identified in 2/251154 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000479458	SCV001363947	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8539G>A (p.Glu2847Lys) results in a conservative amino acid change located in the Tower domain (IPR015205) that is essential for appropriate binding of BRCA2 to DNA. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251154 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8539G>A has been reported in the literature (possibly as a somatic variant), in individuals affected with endometrial cancer and pancreatic cancer (Lu_2015, Pishaian_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been reported in two functional studies to have intermediate HDR activity (Guidugli_2018, Hart_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000564844	SCV002531956	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000113958	SCV004846037	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2847 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported conflicting findings on variant protein function in homology-directed repair assay from loss-of-function to intermediate activities (PMID: 29394989, 29884841). Further, this variant increased sensitivity to PARP inhibitors and decreased cell viability in mouse embryonic stem cells (PMID: 37922907). This variant has been reported in an individual affected with uterine corpus endometrial carcinoma (PMID: 26689913) and also detected in an individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/13-32945144-G-A). This variant has been identified in 2/251154 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	RCV004566851	SCV005059001	uncertain significance	Familial cancer of breast	2024-03-11	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113958	SCV000147397	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-11-10	no assertion criteria provided	clinical testing