Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000795513 | SCV000934978 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 77 of the MLH1 protein (p.Cys77Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 642117). 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 MLH1 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 15475387). This variant disrupts the p.Cys77 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9032648, 15849733, 17510385, 21404117). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Ambry Genetics | RCV002424819 | SCV002731727 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-10-15 | criteria provided, single submitter | clinical testing | The p.C77G variant (also known as c.229T>G), located in coding exon 3 of the MLH1 gene, results from a T to G substitution at nucleotide position 229. The cysteine at codon 77 is replaced by glycine, an amino acid with highly dissimilar properties. This variant was identified in a yeast-based functional genetic screen and demonstrated partial loss of relative mismatch repair activity (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). Based on an internal structural analysis using a published crystal structure, this variant is anticipated to result in disruption of the ATP binding site (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Fulgent Genetics, |
RCV002477808 | SCV002778118 | uncertain significance | Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 | 2022-02-04 | criteria provided, single submitter | clinical testing |