Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000165671 | SCV000216409 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-14 | criteria provided, single submitter | clinical testing | The p.Y2658H variant (also known as c.7972T>C), located in coding exon 16 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7972. The tyrosine at codon 2658 is replaced by histidine, an amino acid with similar properties. This variant was similar to wildtype in a homology-directed DNA repair (HDR) assay (Ambry internal data). However, internal structural analysis indicates that this residue may disrupt an important protein interaction interface (Ambry internal data; Yang H. Science. 2002 Sep;297(5588):1837-48). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |
Labcorp Genetics |
RCV000529353 | SCV000635623 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2025-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2658 of the BRCA2 protein (p.Tyr2658His). 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: 186135). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33609447). 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. |