Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000623903 | SCV000740671 | pathogenic | Lynch syndrome 1 | 2018-03-09 | reviewed by expert panel | curation | Class 5 - Pathogenic Classification using multifactorial probability: 0.997 |
| Genetics and Molecular Pathology, |
RCV003447545 | SCV004175568 | likely pathogenic | Lynch syndrome | 2021-06-15 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003594010 | SCV004312666 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 276 of the MLH1 protein (p.Ile276Arg). 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: 520540). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change affects MLH1 function (PMID: 36054288). 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. |