Submissions for variant NM_000059.4(BRCA2):c.7595C>A (p.Pro2532His)

dbSNP: rs967458408

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538315	SCV000635589	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2532 of the BRCA2 protein (p.Pro2532His). This variant is not present in population databases (gnomAD no frequency). 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: 462448). 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.
Ambry Genetics	RCV001026599	SCV001189014	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-10	criteria provided, single submitter	clinical testing	The p.P2532H variant (also known as c.7595C>A), located in coding exon 14 of the BRCA2 gene, results from a C to A substitution at nucleotide position 7595. The proline at codon 2532 is replaced by histidine, an amino acid with similar properties. This alteration was found to be functional in a homology directed DNA repair assay (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV001255591	SCV001432096	uncertain significance	not specified	2020-08-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7595C>A (p.Pro2532His) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250894 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7595C>A in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.
Baylor Genetics	RCV003476254	SCV004211911	uncertain significance	Familial cancer of breast	2023-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999068	SCV004844433	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine at codon 2532 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study that measured responses to PARP inhibitors has shown inconclusive impact of this variant on BRCA2 function (PMID: 3244479). 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.