Submissions for variant NM_000249.4(MLH1):c.199G>C (p.Gly67Arg)

dbSNP: rs63750206

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589590	SCV000696137	pathogenic	Lynch syndrome	2016-10-27	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.199G>C (p.Gly67Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120848 control chromosomes but has been reported in multiple affected individuals in the literature. In addition, functional studies report the loss of MMR activity (Ellison_2001, Raevaara_2005). Taken together, this variant is classified as pathogenic.
Invitae	RCV000700612	SCV000829374	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly67 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8521398, 12419761, 15563510, 15613555, 17312306, 18383312, 21239990). 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 missense change affects MLH1 function (PMID: 9697702, 11555625, 12810663, 16083711, 18094436, 18337503). 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: 495763). This missense change has been observed in individual(s) with colorectal cancer (PMID: 8521398, 12419761, 15563510, 15613555, 16083711, 17312306, 18383312, 21239990). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 67 of the MLH1 protein (p.Gly67Arg).
Neuberg Centre For Genomic Medicine, NCGM	RCV003388588	SCV004100531	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2		criteria provided, single submitter	clinical testing	The missense variant p.G67R in MLH1 (NM_000249.4) has been reported previously in an affected inidvidual (Raevaara TE et al). Functional studies have shown a damaging effect (Avdievich E et al). It has been submitted to ClinVar as Pathogenic.The p.G67R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.G67R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 67 of MLH1 is conserved in all mammalian species. The nucleotide c.199 in MLH1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003388588	SCV004188759	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16083711, 16982745, 20020535, 22736432]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. This variant is expected to disrupt protein structure [Myriad internal data].