ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.244A>G (p.Thr82Ala) (rs587778998)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490565 SCV000106599 likely pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probability > 0.95 (0.965)
Ambry Genetics RCV000166056 SCV000216818 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-28 criteria provided, single submitter clinical testing The p.T82A variant (also known as c.244A>G), located in coding exon 3 of the MLH1 gene, results from an A to G substitution at nucleotide position 244. The threonine at codon 82 is replaced by alanine, an amino acid with similar properties. This variant has been identified in probands with HNPCC or HNPCC-related cancers and concordant tumors when available (Pastrello C et al. Genet Med. 2011 Feb;13(2):115-24,Hardt K et al. Fam Cancer. 2011 Jun;10(2):273-84, Borras E et al. Hum Mutat. 2012 Nov;33(11):1576-88, Simbolo M et al. Hered. Cancer Clin Pract. 2015 Aug 21;13(1), Ambry internal data). This variant is located in the ATPase functional domain and impaired MMR activity compared to wild-type (Borras E et al. Hum Mutat. 2012 Nov;33(11)). This paper also cites literature demonstrating alterations at the same codon, including p.T82K, p.T82M, and p.T82I, to be defective in MMR activity in yeast and/or human cells. 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 []). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506252 SCV000604231 likely pathogenic not specified 2016-12-27 criteria provided, single submitter clinical testing
Invitae RCV000542720 SCV000625139 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 82 of the MLH1 protein (p.Thr82Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs587778998, ExAC 0.001%). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 21239990, 21404117, 22736432, 26300997, 28514183). ClinVar contains an entry for this variant (Variation ID: 90116). Experimental studies have shown that this missense change significantly reduced DNA mismatch repair activity of MLH1 (PMID: 22736432). The p.Thr82 amino acid residue in MLH1 has been determined to be clinically significant (PMID: 10422993, 20587412, 19690142, 17510385, 23403630). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075602 SCV000696155 likely pathogenic Lynch syndrome 2016-03-14 criteria provided, single submitter clinical testing Variant summary: This c.244A>G variant affects a conserved nucleotide, resulting in amino acid change from Thr to Ala. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 1/122056 control chromosomes from the broad and large populations of ExAC at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0007105) in this gene. This variant has been reported in multiple patients (at least five independent occurrences) affected with HNPCC or HNPCC-related cancers. There are no reported cosegregation studies for this variant. The variant has been functionally characterized to impair the MMR activity, strongly suggesting for pathogenic outcome. Multiple clinical laboratories as well as reputable databases have classified this variant as likely pathogenic. Multifactorial likelihood analysis for the variant is also in line with likely pathogenic outcome. Taken together this variant has currently been classfied as a Probable Disease Variant/Likely Pathogenic.
Color Health, Inc RCV000166056 SCV000908603 pathogenic Hereditary cancer-predisposing syndrome 2020-08-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine 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). Functional studies have shown that the mutant protein shows <10% of normal DNA-mismatch repair activity in vitro (PMID: 22736432, 31881334) (PMID: 22736432, 31881334). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21239990, 26300997) and in individuals affected with colorectal cancer with tumors showing microsatellite instability (PMID: 21404117, 22736432). This variant has been identified in 2/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant p.Thr82Ile is known to be pathogenic, indicating the importance of threonine residue at this position for MLH1 function. Based on the available evidence, this variant is classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353582 SCV000592341 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Thr82Ala variant has been previously reported in the literature and by our laboratory. It was identified in one individual who was reported to have high microsatellite instability and was MLH1 deficient. In addition, it was shown to segregate in one affected family member (Pastrello_2011_21239990). Our laboratory has identified this variant in one family and the variant segregated with disease in 5 affected individuals. Although the pattern of MSI and IHC deficient tumours was inconsistent across individuals from this family, the observation of this variant segregating with Lynch syndrome related cancers increases the likelihood this variant is pathogenic. In addition, functional studies in yeast demonstrated that different variants at this same amino acid residue (T82S, T82K, T82M) were associated with a loss of mismatch repair function between 8% and 67%, increasing the likelihood that this variant may affect normal protein function (Ellison_2004_15475387). In summary, based on the above information, this variant is classified as pathogenic.

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