Submissions for variant NM_000059.4(BRCA2):c.7580T>C (p.Val2527Ala)

dbSNP: rs587782676

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132102	SCV000187167	likely benign	Hereditary cancer-predisposing syndrome	2020-02-25	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508502	SCV000600757	uncertain significance	not specified	2016-10-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637450	SCV000758909	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine with alanine at codon 2527 of the BRCA2 protein (p.Val2527Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 142729). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV000132102	SCV001344654	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-10	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 2527 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. An online preprint reported this variant to be functional in a homology-mediated DNA report assay (https://doi.org/10.1101/792754). This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Fulgent Genetics, Fulgent Genetics	RCV005008040	SCV005633969	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-04-20	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV005365038	SCV005921314	uncertain significance	Pancreatic cancer, susceptibility to, 2	2025-04-19	criteria provided, single submitter	clinical testing	A heterozygous missense variant in exon 15 of the BRCA2 gene that results in an amino acid substitution of Alanine for Valine at codon 2527 was detected. The observed variant c.7580T>C (p.Val2527Ala) has a MAF of 0.0001% in the gnomAD database. The in-silico predictions of this variant are possibly deleterious by LRT, SIFT and MutationTaster. It has a CADD score of 27.1 and is previously reported in the ClinVar database (VAV000142729.17). The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.