ClinVar Genomic variation as it relates to human health

Multifactorial likelihood analysis posterior probability >0.99

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17510385]. This variant is expected to disrupt protein structure [Myriad internal data].

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals/families with Lynch syndrome (PMIDs: 28135145 (2017), 21404117 (2011), 19669161 (2010), 15849733 (2005), 9032648 (1997)), and is classified as pathogenic in a multifactorial analysis study (PMID: 22949379 (2013)). Functional studies also indicate this variant has deleterious effects on MLH1 protein expression and DNA mismatch repair activity (PMIDs: 17510385 (2007), 17210669 (2007), 17135187 (2006), 12810663 (2003), 9697702 (1998)). Based on the available information, this variant is classified as pathogenic.

The p.C77Y pathogenic mutation (also known as c.230G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 230. The cysteine at codon 77 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been identified in numerous individuals meeting Amsterdam criteria for Lynch syndrome with concordant tumor microsatellite and immunohistochemistry results (Hardt Ket al. Fam. Cancer. 2011 Jun; 10(2):273-84; Fokkema IF et al. Hum. Mutat. 2011 May; 32(5):557-63). Functional studies of the p.C77Y alteration have demonstrated impaired/reduced MLH1 expression, sub-cellular localization, and mismatch repair activity compared to wild-type MLH1 protein (Takahashi M et al. Cancer Res. 2007 May; 67(10):4595-604; Kondo E et al. Cancer Res. 2003 Jun; 63(12):3302-8; Wanat JJ et al. Hum. Mol. Genet. 2007 Feb;16(4):445-52; Shimodaira H et al. Nat. Genet. 1998 Aug; 19(4):384-9; Plotz G et al. Nucleic Acids Res. 2006;34(22):6574-86). Functional studies of another amino acid change at the same codon, p.C77R, have also shown impaired activity compared to wild-type (Nystrom-Lahti M et al. Genes Chromosomes Cancer. 2002 Feb;33(2):160-7; Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49). In addition, the p.C77Y alteration has been classified as definitely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

ACMG criteria used to clasify this variant: PM2, PM5, PS3, PM1, PS4

This missense variant replaces cysteine with tyrosine at codon 77 in the ATPase domain 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 shown that this variant reduces protein expression and stability, reduces the dominant negative mutator effect, and reduces DNA mismatch repair activity (PMID: 9697702, 12810663, 17210669, 17510385, 31697235). This variant has been reported in multiple individuals affected with Lynch Syndrome (PMID: 9032648, 15849733, 18383312, 21404117, 25420488, 26895986). 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.

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 77 of the MLH1 protein (p.Cys77Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary non-polyposis colorectal cancer (PMID: 9032648, 15849733, 17510385, 21404117). ClinVar contains an entry for this variant (Variation ID: 90112). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 12810663, 17135187, 17210669, 17510385, 18383312, 22949379, 22949387). This variant disrupts the p.Cys77 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11793442, 16083711, 18383312, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces cysteine with tyrosine at codon 77 in the ATPase domain 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 shown that this variant reduces protein expression and stability, reduces the dominant negative mutator effect, and reduces DNA mismatch repair activity (PMID: 9697702, 12810663, 17210669, 17510385, 31697235). This variant has been reported in multiple individuals affected with Lynch Syndrome (PMID: 9032648, 15849733, 18383312, 21404117, 25420488, 26895986). 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.