ClinVar Genomic variation as it relates to human health

Multifactorial likelihood analysis posterior probability >0.99

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu622 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1749856, 21404117; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects MLH1 protein function (PMID: 17210669, 17510385, 20533529, 20858721, 23403630, 30998989). 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. ClinVar contains an entry for this variant (Variation ID: 29657). This variant has been observed in individual(s) with Lynch syndrome (PMID: 11748856, 20858721, 23523604). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with histidine at codon 622 of the MLH1 protein (p.Leu622His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine.

The p.L622H pathogenic mutation (also known as c.1865T>A), located in coding exon 16 of the MLH1 gene, results from a T to A substitution at nucleotide position 1865. The leucine at codon 622 is replaced by histidine, an amino acid with similar properties. In one study, this mutation was detected in 12 Spanish families with Lynch-related tumors that demonstrated high microsatellite instability (MSI-H) and/or loss of MLH1 expression on immunohistochemistry (IHC), and met Amsterdam criteria. Haplotype analysis confirmed that all families carried the same ancestral allele, strongly supporting p.L622H as a founder mutation of Spanish origin (Borràs E et al. Cancer Res, 2010 Oct;70:7379-91). This alteration is identified in additional Spanish individuals whose Lynch-related tumors demonstrated MSI-H and/or loss of MLH1 expression on IHC, and family history met Amsterdam criteria (Godino J et al. Hum. Mutat., 2001 Dec;18:549; Pérez-Cabornero L et al. Cancer Prev Res (Phila), 2011 Oct;4:1546-55). Based on internal structural analysis using published crystal structures, L622H is more disruptive to the MLH1 C-terminal domain than nearby internally pathogenic variants (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5; Ambry internal data). In two functional studies, this alteration demonstrated proficient MMR activity and intermediate expression (Takahashi M et al. Cancer Res, 2007 May;67:4595-604; Hinrichsen I et al. Clin Cancer Res, 2013 May;19:2432-41); however, in another functional study, this alteration demonstrated reduced MMR activity and expression compared to wild-type MLH1 (González-Acosta M et al. J Mol Diagn, 2020 03;22:376-385). This variant is considered to be rare based on population 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

This missense variant replaces leucine with histidine at codon 622 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have demonstrated that this variant results in reduced expression and stability of the MLH1 protein, but the mutant protein had sufficient mismatch repair activity compared to wild type (PMID: 17510385, 23403630). This variant has been reported in over 20 affected individuals from more than 10 different families with Lynch syndrome (PMID: 20858721, 21778331). This variant has been described as a Spanish founder mutation (PMID: 20858721), and it has been shown that this variant segregates with disease in multiple families (PMID: 20858721). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.