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 Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification
Invitae RCV000791351 SCV000543614 pathogenic Hereditary nonpolyposis colon cancer 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075490 SCV000592436 pathogenic Lynch syndrome 2014-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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