ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1742C>T (p.Pro581Leu) (rs63751684)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115466 SCV000185318 likely benign Hereditary cancer-predisposing syndrome 2017-06-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Does not segregate with disease in family study (genes with incomplete penetrance),Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034540 SCV000043325 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000115466 SCV000684768 likely benign Hereditary cancer-predisposing syndrome 2015-08-04 criteria provided, single submitter clinical testing
GeneDx RCV000212543 SCV000149375 likely benign not specified 2017-12-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000034540 SCV000696125 likely benign not provided 2016-12-23 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1742C>T (p.Pro581Leu) variant located in the carboxyl-terminal (via Fan_2007) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 18/121258 (1/6738), predominantly in the East Asian cohort, 12/8596 (1/716), which does exceed the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. Therefore, suggesting the variant is a benign polymorphism found in population(s) of East Asian origin. Multiple publications cite the variant in affected individuals, however, co-occurrence and/or cosegregation data was not provided, along with predominantly only MLH1 and MSH2 being screened for variants. A functional study, Fan_2007, does suggest that the variant could weaken MLH1-PMS2 binding, however it has yet to confirmed by independent studies. Multiple reputable clinical diagnostic laboratories/databases cite the variant with conflicting classifications "uncertain significance" or "likely benign." One reputable database, InSiGHT, cites the variant and indicates the variant co-occurred with another pathogenic MLH1 variant in trans, did not segregate with disease in a family, and MLH1 protein was preserved. Therefore, due to the frequency in the East Asian control cohort (to which multiple publications citing the variant in affected individuals were from Asian descent), reported co-occurrence with another pathogenic MLH1 variant, lack of cosegregation, support a "benign" classification, although to factor in the observed affects on MLH1 protein function by Fan_2007, the variant of interest has been classified as "likely benign," until additional information becomes available.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075343 SCV000106337 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049. No CMMRD phenotype with co-occurrence & MAF 0.01-1%.
Invitae RCV000524248 SCV000218940 likely benign Hereditary nonpolyposis colon cancer 2017-12-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212543 SCV000539642 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple papers in HGMD, isolated cases and some reference identification in control datasets; ExAC: 0.1% (12/8596) East Asian chromosomes

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