ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1943C>T (rs63750610)

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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) RCV000075433 SCV000106429 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 (0.989)
Ambry Genetics RCV000221413 SCV000278137 pathogenic Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing The p.P648L pathogenic mutation (also known as c.1943C>T) is located in exon 17 of the MLH1 gene. This alteration results from a C to T substitution at nucleotide position 1943. The proline at codon 648 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual diagnosed with microsatellite unstable colorectal cancer at 43 (Raevaara et al. Gastroenterology 2005 Aug; 129(2): 537-49) as well as in cohorts of Lynch syndrome patients and families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). (Dudley B et al. Am. J. Surg. Pathol., 2015 Aug;39:1114-20). Functional studies demonstrated decreased protein expression and localization, but intact MMR function. In another study, this alteration showed a negative dominant mutator effect in yeast with MMR activity of 39.2% and MLH1 expression of 25-75% compared to wild type (Takahashi et al. Cancer Res 2007 May 15; 67(10): 4595-604). Another alteration in the same codon, p.P648S, has also been identified in HNPCC/Lynch syndrome families and shown to disrupt interaction between MLH1 and PMS2 in vitro (Bisgaard et al. Hum Mut 2002 Jul; 20(1): 20-7; Raevaara et al. Genes Chromosomes Cancer 2004 Jul; 40(3): 261-5; Belvederesi et al. Eur J Hum Genet 2006 Jul; 14(7): 853-9; Ou et al. Hum Mut 2007 Nov; 28(11): 1047-54). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence and functional studies (Thompson B et al. Hum Mutat. 2013 Jan;34(1):200-9; Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at []). Based on protein sequence alignment, 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000812087 SCV000952391 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-06-07 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 648 of the MLH1 protein (p.Pro648Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome (PMID: 16083711, 11726306, 21404117, Invitae). ClinVar contains an entry for this variant (Variation ID: 89953). This variant has been reported to affect MLH1 protein function (PMID:20533529, 21404117, 16083711, 17510385, 22753075). This variant disrupts the p.Pro648 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been observed in individuals with MLH1-related conditions (PMID: 15139004, 21404117, 18307539, 16724012, 16083711), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000221413 SCV001343104 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 648 of the MLH1 protein. The reference amino acid proline 648 is conserved across species (PMID: 12519945, 22908213) and computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that this variant causes reduced MLH1 protein expression and decreased binding to PMS2, although the variant impact on MMR activity is inconclusive (PMID: 16083711, 17510385, 20020535, 20533529, 21404117, 22753075, 23403630). This variant has been reported in three individuals from two families affected with colorectal cancer whose tumors showed features of loss of DNA mismatch repair function (PMID: 16083711, 20020535, 21404117, 23403630, 25871621), and it has been observed in an additional individual with suspected Lynch syndrome (PMID: 27601186). Different variants affecting the same position (p.Pro648Ser and p.Pro648Arg) are considered to be disease-causing (ClinVar variation ID: 17097, 479696). 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.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV001269952 SCV001450330 pathogenic not provided 2016-10-13 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477957 SCV000536722 likely pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2016-02-22 no assertion criteria provided research

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