Submissions for variant NM_000059.4(BRCA2):c.9577A>G (p.Thr3193Ala)

dbSNP: rs2073041117

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193237	SCV001361963	uncertain significance	not specified	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9577A>G (p.Thr3193Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251424 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.9577A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341994	SCV001535894	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 3193 of the BRCA2 protein (p.Thr3193Ala). 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: 928796). 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.
GeneDx	RCV001574665	SCV001801526	uncertain significance	not provided	2020-08-31	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV002258149	SCV002532051	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
Ambry Genetics	RCV002258149	SCV005548598	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-20	criteria provided, single submitter	clinical testing	The p.T3193A variant (also known as c.9577A>G), located in coding exon 25 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9577. The threonine at codon 3193 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. Based on the available evidence, the clinical significance of this variant remains unclear.