ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.55A>T (p.Ile19Phe) (rs63750648)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162610 SCV000213038 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075763 SCV000592328 pathogenic Lynch syndrome 2013-01-23 criteria provided, single submitter clinical testing
GeneDx RCV000483320 SCV000565139 likely pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.55A>T at the cDNA level, p.Ile19Phe (I19F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATC>TTC). This variant has been observed in individuals with colorectal or other Lynch-associated cancers meeting revised Bethesda or Amsterdam II criteria (Andrew 2002, Kurzawski 2002, Perera 2010, Yurgleun 2017). In one family, this variant was shown to segregate with colorectal cancer in three siblings (Andrew 2002). A human-yeast hybrid assay demonstrated MLH1Ile19Phe to exhibit partial loss of mismatch repair function (Ellison 2004). MLH1 Ile19Phe was not observed in large population cohorts (Lek 2016). This variant is located within the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence and internal data, we consider MLH1 Ile19Phe to be likely pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680175 SCV000106771 pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability > 0.95 (0.997)
Invitae RCV000791372 SCV000543595 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 19 of the MLH1 protein (p.Ile19Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome associated cancers (PMID: 12362047, 20864636, 28135145), and in three siblings of a family affected with colorectal and ovarian cancer (PMID: 12537657). ClinVar contains an entry for this variant (Variation ID: 90274). An experimental study showed that this missense change leads to an intermediate mutator phenotype in a yeast model (PMID: 15475387). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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