Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075374 | SCV000106369 | uncertain significance | Lynch syndrome 1 | 2018-06-13 | reviewed by expert panel | curation | Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. (0.799) |
| Ambry Genetics | RCV002408580 | SCV002712067 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-23 | criteria provided, single submitter | clinical testing | The p.A608D variant (also known as c.1823C>A), located in coding exon 16 of the MLH1 gene, results from a C to A substitution at nucleotide position 1823. The alanine at codon 608 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant was reported in a Chinese HNPCC family that met Bethesda guidelines and the colorectal tumor of the proband demonstrated low microsatellite instability (MSI-L) (Sheng JQ et al. Cytogenet. Genome Res., 2008 Oct;122:22-7). This variant was also identified in a Norwegian family that met Amsterdam II criteria for Lynch Syndrome and the variant co-segregated with disease in two family members. Furthermore, tumor testing revealed loss of MLH1 and PMS2 expression on immunohistochemistry (IHC) (Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85). In an in vitro complementation assay, this variant had reduced mismatch repair activity compared to wild type MLH1 (Drost M et al. Genet. Med., 2019 Jul;21:1486-1496). Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV002514343 | SCV003525135 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-10-03 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 89897). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 18931482, 20587412, 23640085; Invitae). 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. 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 is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 608 of the MLH1 protein (p.Ala608Asp). |