ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.595G>A (p.Ala199Thr)

gnomAD frequency: 0.00001  dbSNP: rs376582345
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132207 SCV000187289 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-29 criteria provided, single submitter clinical testing The p.A199T variant (also known as c.595G>A), located in coding exon 6 of the BRCA2 gene, results from a G to A substitution at nucleotide position 595. The alanine at codon 199 is replaced by threonine, an amino acid with similar properties. This alteration was previously reported in 1 of 1398 unilateral breast cancer cases and 1 of 705 bilateral breast cancer cases in a population based cohort (Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40). This amino acid position is highly 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 alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000228169 SCV000283279 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 199 of the BRCA2 protein (p.Ala199Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 91429). 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 RCV003325457 SCV004031841 uncertain significance not provided 2023-09-01 criteria provided, single submitter clinical testing Observed in individuals with bilateral or unilateral breast cancer in published literature (Borg et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 823G>T; This variant is associated with the following publications: (PMID: 31853058, 29884841, 31911673, 32377563, 20104584)
Baylor Genetics RCV004566936 SCV005059006 uncertain significance Familial cancer of breast 2024-03-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076946 SCV000108743 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2009-03-26 no assertion criteria provided clinical testing

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