ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.245C>T (p.Thr82Ile) (rs63750005)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075604 SCV000106601 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000222555 SCV000275627 pathogenic Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing The p.T82I pathogenic mutation (also known as c.245C>T), located in coding exon 3 of the MLH1 gene, results from a C to T substitution at nucleotide position 245. The threonine at codon 82 is replaced by isoleucine, an amino acid with similar properties. This mutation has been identified in multiple HNPCC/Lynch syndrome families meeting Amsterdam I/II criteria (Syngal S et al. JAMA. 1999 Jul;282(3):247-53; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85; Ambry internal data). Additionally, functional studies have demonstrated that this alteration leads to a loss of function (Syngal S et al. JAMA. 1999 Jul;282(3):247-53) and reduced repair activity and expression compared to wild-type (Hinrichsen I et al. Clin. Cancer Res. 2013 May;19(9):2432-41). In another study, expression of the variant protein was normal (>75%), but p.T82I showed a dominant negative mutator effect in one of the yeast assays with in vitro MMR activity of 27.2%. This particular mutation is located in a residue thought to be critical for ATP binding and other variants around the pocket were also shown to affect both dominant mutator effect and in vitro MMR activity (Takahashi M et al. Cancer Res. 2007 May;67(10):4595-604). Lastly, this alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat. Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Invitae RCV000630024 SCV000750980 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 82 of the MLH1 protein (p.Thr82Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 10422993, 20587412, 19690142, 28514183). ClinVar contains an entry for this variant (Variation ID: 90118). Experimental studies have shown that this missense change disrupts the mismatch repair activity of the MLH1 protein (PMID: 17510385, 23403630). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659867 SCV000781750 likely pathogenic Lynch syndrome II 2016-11-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075604 SCV000917647 pathogenic Lynch syndrome 2018-04-19 criteria provided, single submitter clinical testing Variant summary: MLH1 c.245C>T (p.Thr82Ile) results in a non-conservative amino acid change located in the Histidine kinase/HSP90-like ATPase domain (IPR003594) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246192 control chromosomes (in gnomAD). c.245C>T has been reported in the literature in individuals affected with Lynch Syndrome. These data indicate that the variant may be associated with the disease (Syngal 1999, Sjursen 2010). Publications reporting experimental evidence evaluating an impact on protein function, showed that the expression of the variant protein is largely preserved (indicating that protein stability is not significantly affected by the variant), however the MMR activity was critically decreased, with the most pronounced variant effect resulting in <10% of normal activity (Takahashi 2007, Hinrichsen 2013). These data are in agreement with the observed normal protein expression (IHC positivity) and microsatellite instability (MSI-High) reported for tumor samples from affected patients carrying the variant (Sjursen 2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Health, Inc RCV000222555 SCV001340976 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing

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