Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV000502902 | SCV000592369 | uncertain significance | not specified | 2014-02-19 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001025837 | SCV001188101 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-16 | criteria provided, single submitter | clinical testing | The c.694G>A pathogenic mutation (also known as p.G232R), located in coding exon 9 of the MLH1 gene, results from a G to A substitution at nucleotide position 694. The glycine at codon 232 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability or loss of MLH1/PMS2 expression by immunohistochemistry (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Ambry internal data). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV002527178 | SCV003225337 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 232 of the MLH1 protein (p.Gly232Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 21404117; Invitae). ClinVar contains an entry for this variant (Variation ID: 433854). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in skipping of exon 9 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |