Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000553834 | SCV000625050 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-10-18 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 41 of the MLH1 protein (p.Asp41Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 19419416; Invitae). ClinVar contains an entry for this variant (Variation ID: 455379). 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. This variant disrupts the p.Asp41 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 25060679, 25477341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000571853 | SCV000673820 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-07-14 | criteria provided, single submitter | clinical testing | The p.D41V pathogenic mutation (also known as c.122A>T), located in coding exon 2 of the MLH1 gene, results from an A to T substitution at nucleotide position 122. The aspartic acid at codon 41 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been detected in multiple families meeting Amsterdam I criteria (Ambry internal data). Based on internal structural analysis, p.D41V is structurally deleterious (Ambry internal data; Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). An alteration resulting in the same amino acid change, p.D41V (c.122_123delATinsTA) has been reported in 1 of 93 unrelated Taiwanese families that fulfilled the Amsterdam II criteria with concordant MSI and/or IHC, and was not found in 300 controls (Tang R et al, Clin. Genet. 2009 Apr; 75(4):334-45). Further, an alteration at the same codon, p.D41G (c.122A>G) has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV003449521 | SCV004185561 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-18 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. |
| Baylor Genetics | RCV003449521 | SCV005057951 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2024-03-24 | criteria provided, single submitter | clinical testing |