Submissions for variant NM_000249.4(MLH1):c.245C>T (p.Thr82Ile)

dbSNP: rs63750005

Total submissions: 8

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	2021-09-16	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	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr82Ala amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21239990, 21404117, 22736432, 26300997, 28514183). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17510385, 23403630). 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. ClinVar contains an entry for this variant (Variation ID: 90118). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 10422993, 19690142, 20587412, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 82 of the MLH1 protein (p.Thr82Ile).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659867	SCV000781750	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778703	SCV000917647	pathogenic	Hereditary nonpolyposis colon cancer	2021-10-04	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 N-terminal domain (IPR002099) 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 251394 control chromosomes (gnomAD). c.245C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Syngal_1999, Sjursen_2010, Guindalini_2015, Sarode_2019, Li_2020). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in decreased MMR activity (Takahashi 2007, Hinrichsen 2013). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=1) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000222555	SCV001340976	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-14	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 82 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes a significant decrease in mismatch repair activity (PMID: 17510385, 23403630). This variant has been reported in individuals affected with affected with Lynch syndrome (PMID: 10422993) or suspected of having Lynch syndrome (PMID: 19690142, 28514183). This variant has been shown to segregate with disease in six related individuals in a family (PMID: 20587412). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV000659867	SCV004193062	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-01-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477470	SCV004220879	pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	This missense variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with Lynch syndrome (PMID:1042293 (1999), PMID:17510385 (2007), PMID:19690412 (2010), PMID:26248088 (2015), PMID:30917047 (2019)). The variant has also been reported to decrease protein function in vitro (PMID:23403630 (2013)).Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.