ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.731G>A (p.Gly244Asp) (rs63750303)

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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) RCV000075830 SCV000106844 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000573119 SCV000673849 pathogenic Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV000075830 SCV000919647 pathogenic Lynch syndrome 2017-09-21 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.731G>A (p.Gly244Asp) variant involves the alteration of a conserved nucleotide that results in a non-conservative amino acid substitution in the N-terminal part of the MLH1 protein which might be involved in protein interactions (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Published functional studies demonstrated that the variant protein virtually lost the ability to bind to its partner proteins (PMS2 or EXO1) and also resulted in a substantially decreased (19.4% of normal) in vitro MMR activity (Kondo 2003, Takahashi 2007). This variant is absent in 246120 control chromosomes. The variant was reported in multiple patients with colorectal cancer and other LS-associated tumors from Lynch syndrome families, including evidence of cosegregation with disease (e.g. Choi 2009, Bozzao 2011, Barrera 2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color RCV000573119 SCV001349013 pathogenic Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing
Invitae RCV001210008 SCV001381471 pathogenic Hereditary nonpolyposis colon cancer 2019-09-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 244 of the MLH1 protein (p.Gly244Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several families affected with Lynch Syndrome (PMID: 21286823, 9218993, 16982745, 15713769,12658575). ClinVar contains an entry for this variant (Variation ID: 90339). This variant has been reported to affect MLH1 protein function (PMID: 11781295, 16982745, 10082584, 17510385, 12810663). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16995940). This variant disrupts the p.Gly244 amino acid residue in MLH1. Another variant that disrupt this residue have been observed in individuals with MLH1-related conditions (PMID: 21642682, Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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