Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002438211 | SCV002748599 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-03-16 | criteria provided, single submitter | clinical testing | The p.L979P variant (also known as c.2936T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 2936. The leucine at codon 979 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV005091077 | SCV005817297 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-03-25 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 979 of the MSH6 protein (p.Leu979Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 433917). 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 expected to disrupt MSH6 protein function with a positive 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. |
| Department of Pathology and Laboratory Medicine, |
RCV000502849 | SCV000592618 | uncertain significance | Carcinoma of colon | no assertion criteria provided | clinical testing | The p.Leu979Pro variant was not identified in the literature. The p.Leu979 residue is conserved across mammals and lower organisms but not in yeast, and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) suggest that the p.Leu979Pro variant may impact the protein. The variant also occurs within a recognized protein domain (the DNA mismatch repair protein MutS, core and clamp). However, this information is not predictive enough to assume the variant is pathogenic. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. |