Submissions for variant NM_000059.4(BRCA2):c.7597T>G (p.Ser2533Ala)

dbSNP: rs786204150

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168141	SCV000218801	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2533 of the BRCA2 protein (p.Ser2533Ala). 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: 188212). 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%. 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	RCV001026601	SCV001189016	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-13	criteria provided, single submitter	clinical testing	The p.S2533A variant (also known as c.7597T>G), located in coding exon 14 of the BRCA2 gene, results from a T to G substitution at nucleotide position 7597. The serine at codon 2533 is replaced by alanine, 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.
Baylor Genetics	RCV003462258	SCV004213591	uncertain significance	Familial cancer of breast	2023-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700518	SCV005202240	uncertain significance	not specified	2024-07-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7597T>G (p.Ser2533Ala) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250848 control chromosomes. 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.7597T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 188212). Based on the evidence outlined above, the variant was classified as uncertain significance.