Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001202105 | SCV001373206 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2025-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 636 of the MLH1 protein (p.Leu636Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15365995). ClinVar contains an entry for this variant (Variation ID: 89940). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 20533529, 31784484). 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. |
| Ambry Genetics | RCV002408585 | SCV002719937 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-14 | criteria provided, single submitter | clinical testing | The p.L636P variant (also known as c.1907T>C), located in coding exon 17 of the MLH1 gene, results from a T to C substitution at nucleotide position 1907. The leucine at codon 636 is replaced by proline, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal history that is consistent with Lynch syndrome (Shin YK et al. Hum Mutat, 2004 Oct;24:351). Functional studies have demonstrated reduced protein stability compared to wild-type MLH1 (Kosinski J et al. Hum Mutat, 2010 Aug;31:975-82; Houlleberghs H et al. J Med Genet, 2020 May;57:308-315). This variant has been identified in a proband who met Amsterdam I criteria for Lynch syndrome (Ambry internal data). This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (external laboratory communication). Based on internal structural analysis, L636P is deleterious; the variant is moderately destabilizing to the local structure (Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
| Myriad Genetics, |
RCV003451080 | SCV004189174 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-24 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20533529, 31784484]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15365995]. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV004689444 | SCV005184355 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-04-09 | criteria provided, single submitter | curation | According to the ACMG SVI adaptation criteria we chose these criteria: PS3 (medium pathogenic): Kosinski 2010: statistically significant reduction of relative MLH1expression (25-75%) but MMR activity >60% compared to wild type Houlleberghs 2020: methylation-damage-induced mutagenesis events and slippage rate/MMR capacity at similar rates as the MMR-deficient S44F pathogenic control, PM2 (supporting pathogenic): Absent from controls, PP3 (supporting pathogenic): REVEL: O.975 |