ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1964T>C (p.Ile655Thr) (rs63751225)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128924 SCV000172794 likely benign Hereditary cancer-predisposing syndrome 2017-10-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),In silico models in agreement (benign),Other data supporting benign classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034544 SCV000043329 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER_CC_NCGL; University of Washington Medical Center RCV000148623 SCV000190338 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Color RCV000128924 SCV000910738 likely benign Hereditary cancer-predisposing syndrome 2015-07-20 criteria provided, single submitter clinical testing
Counsyl RCV000662533 SCV000785103 uncertain significance Lynch syndrome II 2017-04-18 criteria provided, single submitter clinical testing
GeneDx RCV000034544 SCV000211118 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1964T>C at the cDNA level, p.Ile655Thr (I655T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has been identified in several individuals with colorectal cancer and a family history suspicious of Lynch syndrome, and at least one individual with gastric cancer (Keller 1996, Ravnik-Glavac 2000, Potocnik 2001, Giraldo 2005, Irmejs 2007). This variant was identified in the germline of an individual whose colon tumor showed microsatellite instability, but was also positive for MLH1 promoter hypermethylation and did not show loss of heterozygosity (Potocnik 2001). In addition, this variant was observed in one individual with atherosclerosis, with no specific information about cancer history (Johnston 2012). In vitro functional studies demonstrated this variant performs similar to wild type with regards to dominant-mutator effect, mismatch repair activity, and MLH1 expression (Takahashi 2007). MLH1 Ile655Thr was observed at an allele frequency of 0.0166% (21/126,516) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ile655Thr is located in the PMS2/MLH3/PMS1 interaction region (Raevaara 2005, Kansikas 2011, Andersen 2012). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Ile655Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000128924 SCV000822021 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781539 SCV000919656 uncertain significance not specified 2017-12-15 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1964T>C (p.Ile655Thr) variant located in the DNA mismatch repair protein Mlh1, C-terminal domain involves the alteration of a conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study, Takahashi_2007, found the variant to have 73.8% in vitro MMR activity. This variant was found in 26/277186 control chromosomes (gnomAD and publication controls), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000166 (21/126516). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). Multiple publications have cited the variant in affected individuals, however, with limited information (ie, lack of cosegregation and/or co-occurrence data), although one publication, Potocnik_2011, cites the variant to occur in a sample with MLH1 promoter methylation. In addition, multiple clinical diagnostic laboratories/reputable databases cite this variant with conflicting classifications, "uncertain significance" or "likely benign." Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075441 SCV000106438 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524260 SCV000284039 likely benign Hereditary nonpolyposis colon cancer 2017-12-19 criteria provided, single submitter clinical testing

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