Submissions for variant NM_000059.4(BRCA2):c.5702A>T (p.Glu1901Val)

gnomAD frequency: 0.00001  dbSNP: rs773600818

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166961	SCV000217782	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-23	criteria provided, single submitter	clinical testing	The p.E1901V variant (also known as c.5702A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5702. The glutamic acid at codon 1901 is replaced by valine, an amino acid with dissimilar properties. This variant was reported in multiple individuals with a personal history of breast and/or ovarian cancer (Zuntini R et al. Front Genet, 2018 Sep;9:378; Stella S et al. Genes (Basel), 2024 Jul;15:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531229	SCV000635465	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-23	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 1901 of the BRCA2 protein (p.Glu1901Val). This variant is present in population databases (rs773600818, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 30254663, 35150867). ClinVar contains an entry for this variant (Variation ID: 187246). 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%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000166961	SCV000683726	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1901 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 at least one individual with a personal or family history of breast and/or ovarian cancer (PMID: 30254663, 35150867) and in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.54, 1.025, and 0.375, respectively (PMID: 31131967). This variant has been identified in 3/250802 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.
Counsyl	RCV000663324	SCV000786596	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-06-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166961	SCV002536164	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-16	criteria provided, single submitter	curation
GeneDx	RCV002464137	SCV002758969	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Identified in an individual fulfilling BRCA testing criteria (Zuntini et al., 2018); 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; Also known as 5930A>T; This variant is associated with the following publications: (PMID: 31853058, 31131967, 32377563, 30254663, 29884841)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166961	SCV003849026	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	RCV000663324	SCV004846628	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1901 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 30254663). This variant has also been identified in 3/250802 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	RCV004700512	SCV005203879	uncertain significance	not specified	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5702A>T (p.Glu1901Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250802 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5702A>T has been reported in the literature in an individual affected with breast or ovarian cancer (Zuntini_2018) and an individual with pancreatic cancer (Militello_2023) without evidnece of causality. These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 30254663, 37725113). ClinVar contains an entry for this variant (Variation ID: 187246). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002464137	SCV005624468	uncertain significance	not provided	2024-02-29	criteria provided, single submitter	clinical testing	The BRCA2 c.5702A>T (p.Glu1901Val) variant has been reported in the published literature in individuals with a hereditary breast and ovarian (HBOC) syndrome related cancer (PMID: 35150867 (2022), 31853058 (2020), 30254663 (2018)). In addition, this variant has been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000026 (3/113320 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Medical and Surgical Sciences, University of Bologna	RCV000663324	SCV004228418	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)