Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Foundation for Research in Genetics and Endocrinology, |
RCV000984470 | SCV000999005 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2019-09-10 | criteria provided, single submitter | clinical testing | A heterozygous missense variation in exon 2 of the MLH1 gene that results in the amino acid substitution of Valine for Glycine at codon 67 was detected. The observed variant c.200G>T (p.Gly67Val) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by SIFT, LRT, MutationTaster2, Mutation Assessor and FATHMM. Three other missense variants p.Gly67Trp, p.Gly67Glu and p.Gly67Arg altering the same codon as the identified variant has been reported as pathogenic in ClinVar database with respect to Lynch syndrome. The said variant alters a highly conserved residue and is predicted to be damaging to the protein function. |
Invitae | RCV002549626 | SCV003218006 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-06-13 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly67 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16807412, 18033691, 19142183). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387). 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. ClinVar contains an entry for this variant (Variation ID: 800484). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 67 of the MLH1 protein (p.Gly67Val). |
Myriad Genetics, |
RCV000984470 | SCV004189375 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-12 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16083711, 16982745]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16083711, 18033691]. |