Submissions for variant NM_000249.4(MLH1):c.200G>A (p.Gly67Glu)

dbSNP: rs63749939

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075482	SCV000106478	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000132445	SCV000187539	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	clinical testing	The p.G67E pathogenic mutation (also known as c.200G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 200. The glycine at codon 67 is replaced by glutamic acid, an amino acid with similar properties. This alteration is observed in several individuals whose Lynch-related tumors demonstrated high microsatellite instability and/or loss of MLH1 or MLH1 and PMS2 expression on immunohistochemistry (IHC), and MLH1 promoter hypermethylation was negative (Ambry internal data; Barnetson RA et al. Hum Mutat. 2008 Mar;29(3):367-74). This alteration segregated with disease in multiple colon cancer families, and in one family with many cancers that are atypical for Lynch syndrome (Barnetson RA et al. Hum Mutat. 2008 Mar;29(3):367-74; Clyne M et al. Br J Cancer. 2009 Jan 27;100(2):376-80). In vitro yeast studies indicated that G67E is stably expressed but showed inhibition of protein activity during MMR and was therefore categorized as a loss of function allele (Clyne M et al. Br J Cancer. 2009 Jan 27;100(2):376-80). Based on internal structural analysis using published crystal structures, p.G67E is anticipated to result in a significant decrease in structural stability (Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5; Ambry internal data). 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.
Invitae	RCV000524267	SCV000253790	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 67 of the MLH1 protein (p.Gly67Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 16807412, 18033691, 19142183). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17106). 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: 15475387, 19142183, 24362816). 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, 18337503, 19142183). 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.
GeneDx	RCV000216147	SCV000279068	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Segregates with disease in several families meeting Amsterdam criteria, with tumor studies from some individuals demonstrating microsatellite instability (MSI) and/or loss of MLH1 protein expression (Terdiman et al., 2001; Barnetson et al., 2006; Barnetson et al., 2008; Clyne et al., 2009; Yu et al., 2009; Chubb et al., 2015; Frolova et al., 2015); This variant is associated with the following publications: (PMID: 20459533, 24878972, 23510156, 23741719, 16807412, 15475387, 19142183, 22290698, 22949387, 24362816, 11208710, 16995940, 17939062, 17192056, 19493351, 18033691, 25559809, 20068152, 20668451, 22516243, 29887214, 32081490, 30877237, 30787465, 25617771, 22753075, 16083711, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000132445	SCV001734846	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 67 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 protein impairs DNA mismatch repair activity in yeast-based assays (PMID: 15475387, 19142183). This variant has been reported in individuals affected with colorectal cancer (PMID: 16807412, 18033691), endometrial cancer (PMID: 25617771), prostate cancer (PMID: 18033691), breast cancer (PMID: 18033691, 19142183, 32081490), uveal melanoma (PMID: 32081490), and leiomyosarcoma (PMID: 19142183, 32659967). It has also been reported that this variant segregates with Lynch syndrome-associated cancers in multiple families (PMID: 18033691). 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.
Revvity Omics, Revvity	RCV000216147	SCV003821562	pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing
OMIM	RCV000018641	SCV000038924	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2009-01-27	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000216147	SCV000691842	pathogenic	not provided		no assertion criteria provided	clinical testing