Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| St. |
RCV000761060 | SCV000890975 | uncertain significance | Lynch syndrome | 2020-10-15 | criteria provided, single submitter | clinical testing | The MSH6 c.1657A>C (p.Thr553Pro) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-48026779-A-C). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4. |
| Invitae | RCV001855936 | SCV002291188 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-01-05 | criteria provided, single submitter | clinical testing | 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. 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 MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 620605). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 553 of the MSH6 protein (p.Thr553Pro). |
| Ambry Genetics | RCV003166021 | SCV003867527 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-12 | criteria provided, single submitter | clinical testing | The p.T553P variant (also known as c.1657A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 1657. The threonine at codon 553 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. 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 | RCV003461020 | SCV004195540 | uncertain significance | Endometrial carcinoma | 2023-09-01 | criteria provided, single submitter | clinical testing |