Submissions for variant NM_000059.4(BRCA2):c.8942A>G (p.Glu2981Gly)

gnomAD frequency: 0.00002  dbSNP: rs398122716

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087133	SCV000254222	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510052	SCV000607799	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	The p.E2981G variant (also known as c.8942A>G), located in coding exon 21 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8942. The glutamic acid at codon 2981 is replaced by glycine, an amino acid with similar properties. This alteration was detected once in a cohort of Portuguese breast and ovarian cancer families, and authors classified it as a variant of unknown significance (Peixoto A, et al. Clin. Genet. 2015; 88(1):41-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469007	SCV000695194	uncertain significance	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8942A>G (p.Glu2981Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248100 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8942A>G has been reported in the literature in individuals affected with breast or ovarian cancer and an unaffected control (Peixoto_2014, Solano_2021, Nagy_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.5909C>A, p.Ser1970X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24916970, 34072659, 34287479, 33471991). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign (n=1) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000510052	SCV001351222	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2981 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 performed for this variant. This variant has been reported in at least 2 families/individuals affected with hereditary breast and/or ovarian cancer and has been reported in 1 unaffected individual (PMID 24916970, 33471991, 34072659, 34287479). This variant has been identified in 6/248100 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	RCV000586974	SCV001470463	uncertain significance	not provided	2019-10-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000510052	SCV002531989	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	curation
GeneDx	RCV000586974	SCV002540380	uncertain significance	not provided	2022-06-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9170A>G; This variant is associated with the following publications: (PMID: 24916970, 22144684, 12228710, 28480178, 32422573, 34072659, 34287479)
Baylor Genetics	RCV003460733	SCV004213722	uncertain significance	Familial cancer of breast	2023-07-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077646	SCV004846098	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2981 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 performed for this variant. This variant has been reported in at least 2 families/individuals affected with hereditary breast and/or ovarian cancer and has been reported in 1 unaffected individual (PMID 24916970, 33471991, 34072659, 34287479). This variant has been identified in 6/248100 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)	RCV000077646	SCV000109449	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-19	no assertion criteria provided	clinical testing