Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000033274 | SCV000057179 | uncertain significance | not provided | 2014-05-15 | criteria provided, single submitter | clinical testing | The S122Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S122Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, this substitution occurs at a position that is highly conserved across species. Moreover, in silico analysis predicts this variant is possibly damaging to the protein structure/function. Nevertheless, the S122Y variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, no missense mutations in nearby residues have been reported in association with CFC syndrome, indicating this region of the protein may be tolerant of change. The variant is found in CARDIOMYOPATHY panel(s). |
Invitae | RCV003539762 | SCV004310404 | uncertain significance | RASopathy | 2023-10-29 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 122 of the BRAF protein (p.Ser122Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 40341). 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 BRAF 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. |