Submissions for variant NM_000059.4(BRCA2):c.3329A>T (p.Glu1110Val)

gnomAD frequency: 0.00003  dbSNP: rs587782072

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130562	SCV000185433	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-06	criteria provided, single submitter	clinical testing	The p.E1110V variant (also known as c.3329A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 3329. The glutamic acid at codon 1110 is replaced by valine, an amino acid with dissimilar properties. This alteration has been identified in the tumor of an individual with high grade serous ovarian cancer; however, germline testing was not performed (Schwarz RF et al. PLoS Med. 2015 Feb; 12(2):e1001789). This amino acid position is highly 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.
GeneDx	RCV000478180	SCV000567774	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as c.3557A>T; This variant is associated with the following publications: (PMID: 25710373)
Color Diagnostics, LLC DBA Color Health	RCV000130562	SCV000683547	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1110 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/268100 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637374	SCV000758830	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1110 of the BRCA2 protein (p.Glu1110Val). This variant is present in population databases (rs587782072, gnomAD 0.002%). 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: 141869). 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) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV001193169	SCV001361853	uncertain significance	not specified	2021-11-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3329A>T (p.Glu1110Val) 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 allele was found at a frequency of 8.4e-06 in 236698 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3329A>T has been reported in the literature in one individual affected with high-grade serous ovarian cancer (HGSOC) (Schwarz_2015). This report do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000130562	SCV002533784	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-26	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130562	SCV003851868	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).
All of Us Research Program, National Institutes of Health	RCV003998063	SCV004845145	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1110 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/268100 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.