ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2038T>C (p.Cys680Arg) (rs63750809)

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Total submissions: 5
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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, the in silico prediction for this alteration is inconclusive. Based on the available evidence, p.C680R is classified as a pathogenic mutation.
Invitae RCV000791351 SCV000543614 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-01-14 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 680 of the MLH1 protein (p.Cys680Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with suspected Lynch syndrome (PMID: 18931482, 25077178, 27601186), and several families affected with Lynch syndrome (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 90006). This variant has been reported to affect MLH1 protein 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.
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.

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