ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1918C>T (p.Pro640Ser) (rs63749792)

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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) RCV000075424 SCV000106419 likely pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Abrogated function & >2 MSI-H tumours
Invitae RCV000791363 SCV000254362 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-14 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 640 of the MLH1 protein (p.Pro640Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome (PMID: 15365995, 22854115, 24278394, 24292105), and was reported to segregate with disease in two families (PMID: 16276679, Invitae). ClinVar contains an entry for this variant (Variation ID: 89945). This variant has been reported to affect MLH1 protein function (PMID: 21404117, 23403630). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075424 SCV000592427 likely pathogenic Lynch syndrome 2015-09-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569430 SCV000676063 pathogenic Hereditary cancer-predisposing syndrome 2019-01-29 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV001193959 SCV001363155 likely pathogenic Hereditary nonpolyposis colon cancer 2019-05-14 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1918C>T (p.Pro640Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251338 control chromosomes (gnomAD). c.1918C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (e.g. Giraldo_2005, Kang_2015, Shin_2004, Woo_2014), where in one family co-segregation with the disease was observed (Giraldo_2005), and in several cases microsatellite instable tumor and the loss of MLH1 protein was indicated (Kang_2015, Plummer_2012, and in the UMD database). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant had no impact on splicing (Tournier_2008), however the variant protein had decreased stability, impaired interaction with PMS2 and exhibited about 30% repair activity compared to wild type (Hardt_2011, Hinrichsen_2013). Three submitters, have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as likely pathogenic (2x) and VUS (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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