Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002038998 | SCV002314542 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-07-19 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with Lynch syndrome (PMID: 21404117; Invitae). It has also been observed to segregate with disease in related individuals. 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17135187). 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: 1523598). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 130 of the MLH1 protein (p.Tyr130His). |
| Myriad Genetics, |
RCV003453982 | SCV004185794 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-13 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17135187]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Color Diagnostics, |
RCV003585193 | SCV004359182 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-28 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with histidine at codon 130 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this mutant protein was non-functional in a mismatch repair assay (PMID: 21404117). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21404117; ClinVar SCV002314542.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |