Submissions for variant NM_000249.4(MLH1):c.2038T>G (p.Cys680Gly)

gnomAD frequency: 0.00007  dbSNP: rs63750809

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411388	SCV000488878	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-07-12	criteria provided, single submitter	clinical testing
Invitae	RCV000684822	SCV000543523	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 680 of the MLH1 protein (p.Cys680Gly). This variant is present in population databases (rs63750809, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15345113). ClinVar contains an entry for this variant (Variation ID: 90007). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. This variant disrupts the p.Cys680 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18931482, 23729658, 25077178, 27601186). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000483931	SCV000567226	uncertain significance	not provided	2016-04-12	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.2038T>G at the cDNA level, p.Cys680Gly (C680G) at the protein level, and results in the change of a Cysteine to a Glycine (TGC>GGC). This variant has been reported in a woman with a personal history of four separate malignancies including breast, rectal, colon and ureter (Rajkumar 2004). MLH1 Cys680Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Cys680Gly occurs at a position that is conserved in mammals and is located in the region of interaction with PMS2, MLH3 and PMS1 (Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Cys680Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000579550	SCV000684792	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 680 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with three Lynch syndrome-associated cancers (PMID: 15345113). In a large breast cancer case-control study, this variant was not reported in affected cases and reported in four healthy controls (PMID: 33471991). This variant has been identified in 18/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense mutation at the same codon, p.Cys680Arg, has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 18931482, 23729658, 25077178, 27601186) and shown in a functional study to be defective in DNA mismatch repair in vitro (PMID: 25077178). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000411388	SCV001135006	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-12-07	criteria provided, single submitter	clinical testing	A Heterozygous missense variation in exon 18 of the MLH1 gene that results in the amino acid substitution of Glycine for Cysteine at codon 680 was detected. The observed variant c.2038T>G (p.Cys680Gly) has previously been reported in the patient affected with colorectal cancer and it is documented as likely pathogenic in InSiGHT and ClinVar database. The p.Cys680Gly variant has not been reported in the 1000 Genomes and has a minor allele frequency of 0.01% in the ExAC databases. The in silico predictions of the variant are damaging by SIFT, LRT and MutationTaster2 tools. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic.
Illumina Laboratory Services, Illumina	RCV000411388	SCV001307913	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228179	SCV002511442	uncertain significance	not specified	2022-04-15	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2038T>G (p.Cys680Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251246 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.2e-05 vs 0.00071), allowing no conclusion about variant significance. c.2038T>G has been reported in the literature as a variant of probable significance in one individual with MSI-high colorectal tumor, a personal and family history of HNPCC-related cancers who was reportedly genotyped only for MLH1 and MSH2 genes (example Rajkumar_2004, cited in Bhai_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000579550	SCV002528705	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
Ambry Genetics	RCV000579550	SCV002719722	likely benign	Hereditary cancer-predisposing syndrome	2021-03-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Myriad Genetics, Inc.	RCV000411388	SCV004018195	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Neuberg Centre For Genomic Medicine, NCGM	RCV000411388	SCV004176641	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.2038T>G(p.Cys680Gly) variant in MLH1 gene has been reported in heterozygous state in individuals affected with MLH1 related disorders (Rajkumar T, et. al., 2004; Dominguez-Valentin M, et. al., 2014; Mittal A, et. al., 2022). The variant is reported with an allele frequency of 0.007% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Benign/Likely Pathogenic/Uncertain Significance (multiple submissions). The amino acid change p.Cys680Gly in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 680 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
Baylor Genetics	RCV000411388	SCV004195064	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997122	SCV004843257	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 680 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with three Lynch syndrome-associated cancers (PMID: 15345113). In a large breast cancer case-control study, this variant was not reported in affected cases and reported in four healthy controls (PMID: 33471991). This variant has been identified in 18/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense mutation at the same codon, p.Cys680Arg, has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 18931482, 23729658, 25077178, 27601186) and shown in a functional study to be defective in DNA mismatch repair in vitro (PMID: 25077178). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.