Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000630228 | SCV000751184 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-01-17 | 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 292 of the MLH1 protein (p.Leu292Pro). 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: 16341550; Invitae). ClinVar contains an entry for this variant (Variation ID: 90404). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002371909 | SCV002685880 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-10-13 | criteria provided, single submitter | clinical testing | The p.L292P variant (also known as c.875T>C), located in coding exon 10 of the MLH1 gene, results from a T to C substitution at nucleotide position 875. The leucine at codon 292 is replaced by proline, an amino acid with similar properties. This alteration has been identified in multiple individuals that met clinical criteria for Lynch syndrome (Kurzawski G et al. J. Med. Genet., 2002 Oct;39:E65; Pagenstecher C et al. Hum. Genet., 2006 Mar;119:9-22; Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84; 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. |
| Cancer Variant Interpretation Group UK, |
RCV003235034 | SCV003934870 | likely pathogenic | Lynch syndrome | 2021-09-10 | criteria provided, single submitter | clinical testing | Data included in classification: Revel score 0.959. (PP3_sup) Not observed in gnomAD v2.1. (PM2_sup) UK Family #1: Proband colorectal cancer at ~28 years – MLH1/PMS2 loss on IHC, MLH promoter methylation normal. Somatic mismatch repair panel: MLH1 LOH detected, MLH1 c.875T>C p.(Leu292Pro) 79% VAF (NCC: 30-50%); Literature Family #1: Pagenstecher et al 2006 (PMID: 16341550). Proband colorectal cancer at 34 years, father colorectal cancer at 75 years, grandfather colorectal cancer at 39 years. Proband’s tumour MSI high, MLH1 IHC loss (PMS2 IHC not examined, no MLH1 methylation results); Literature Family #2: Muller et al 2004 (PMID: 15507669). Proband colorectal cancer at 46. Proband’s tumour MSI high, MLH1 IHC loss (PMS2 IHC result not stated, no MLH1 methylation results). (PP4_str). Additional information (not included in classification): Literature Families #3-5: Kurzawski et al 2006 (PMID: 16451135) 3 observations in Polish families with a clinical diagnosis of HNPCC. InSiGHT classification class 3 – uncertain due to insufficient evidence 05/09/2013 Invitae class 3 uncertain significance (2018) |