Submissions for variant NM_000249.4(MLH1):c.2038T>C (p.Cys680Arg)

dbSNP: rs63750809

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075490	SCV000106486	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics	RCV000215088	SCV000277597	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-25	criteria provided, single submitter	clinical testing	The p.C680R pathogenic mutation (also known as c.2038T>C), located in coding exon 18 of the MLH1 gene, results from a T to C substitution at nucleotide position 2038. The cysteine at codon 680 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in a cohort of Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835), and in one Chinese family diagnosed with Lynch syndrome (Sheng JQ et al. Cytogenet. Genome Res. 2008;122(1):22-7). Another study identified this alteration in an individual with four Lynch syndrome-associated tumors; all of which showed microsatellite instability and loss of MLH1 and PMS2 on IHC. The effect of this alteration on MMR function was also assessed by looking at its ability to repair a GT mismatched substrate in a cell-free mismatch repair assay. Authors found the efficiency of this alteration to be comparable to that of another well-described pathogenic MLH1 mutation. Further, a yeast-based assay showed that this alteration does not interact with PMS2 suggesting that the MMR-deficiency is caused by failure to form the essential MutLa complex (Dominguez-Valentin M et al. Mol Genet Genomic Med. 2014 Jul; 2(4):352-5). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.C680R is classified as a pathogenic mutation.
Invitae	RCV000791351	SCV000543614	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 680 of the MLH1 protein (p.Cys680Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 18931482, 23729658, 25077178, 27601186). ClinVar contains an entry for this variant (Variation ID: 90006). 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: 25077178). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075490	SCV000696139	likely pathogenic	Lynch syndrome	2016-01-08	criteria provided, single submitter	clinical testing	Variant summary: The c.2038T>C variant affects a conserved nucleotide, resulting in amino acid change from Cys to Arg. Protein studies confirmed that p.Cys680 resides in a tight hydrophobic cavity and that the p.Cys680Arg mutation disrupts the folding of the C-terminal domain of MLH1 (Bell_2013_abstract). Thus, this missense change may not be tolerated. 3/4 in-silico tools used predict this variant to be damaging. This variant is found exclusively in South Asian population (12/16476 control chromosomes) at a frequency of 0.000728, which is in the similar range with that of the maximal expected frequency of a pathogenic allele (0.0007105) in this gene based on the estimated population prevalence of LS (1/440). The prevalence of LS in South Asian population is not known. From peer-reviewed publications, this variant has been reported in two LS families from different ethnic populations (Sheng_2008, Dominguez-Valentin_2014). Additonally, one conference abstract reported that this variant cosegregated in 12 patients from 2 LS families (Bell_2013). One functional study (Dominguez-Valentin_2014) used yeast two-hybrid and cell-free mismatch repair assays to show that p.Cys680Arg not only affects the formation of MutLalfa complex but also the MMR activity -- a strong data for a pathogenic outcome. With patient and functional data in favor of pathogenicity, the frequency data of this variant in South Asian population alone is not sufficient to rule out pathogenicity in the same or other populations. In addition, multiple reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant has currently been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003451096	SCV004189240	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25077178]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003451096	SCV004193053	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-04-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353998	SCV000592436	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Cys680Arg variant has been previously reported in the literature in one of 76 probands with HNPCC and this individual was MSI high. This report also suggests an affected brother was a carrier and that the variant was not identified in 200 control chromosomes (Sheng_2008_18931482). In addition, this variant has been previously identified by our lab. In two families this variant segregated with disease in a total of 12 individuals and 3 had an MLH1 deficient tumour. In addition, another variant at the same position, p.Cys680Gly, has been observed in one family from India with MSI-High status and multiple Lynch related cancers, suggesting this residue is important for normal protein function (Rajkumar, 2004). In summary, based on the above information, this variant is classified as pathogenic. Well conserved in mammals but not lower organisms and in-silico studies disagree on the classification of this variant.