Submissions for variant NM_000059.4(BRCA2):c.4736C>T (p.Ala1579Val)

dbSNP: rs1555283920

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545121	SCV000635401	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1579 of the BRCA2 protein (p.Ala1579Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 462356). 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 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 (Invitae). 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.
Ambry Genetics	RCV000562970	SCV000666174	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	The p.A1579V variant (also known as c.4736C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 4736. The alanine at codon 1579 is replaced by valine, an amino acid with similar properties. This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health	RCV000562970	SCV000688888	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1579 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 an individual with a family history of prostate cancer (PMID: 35260348). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758899	SCV000887825	uncertain significance	not provided	2019-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469188	SCV002766393	uncertain significance	not specified	2022-11-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4736C>T (p.Ala1579Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251010 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4736C>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least one unaffected individual with a reported family history of prostate cancer in the father and brother (example, Ramamurthy_2022). The genotype status or co-segregation among affected individuals within this family is not specified in this study. These report(s) 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 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000562970	SCV003852059	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).
GeneDx	RCV000758899	SCV004012719	uncertain significance	not provided	2023-01-09	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; Observed in an individual with family history of prostate cancer in first-degree relatives (Ramamurthy et al., 2022); Also known as 4964C>T; This variant is associated with the following publications: (PMID: 35260348)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002469188	SCV005090035	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing