ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.469dup (p.Tyr157fs) (rs63751101)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000583004 SCV000689890 pathogenic Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780415 SCV000917642 likely pathogenic Lynch syndrome 2017-10-10 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.469dupT (p.Tyr157LeufsX15) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1210_1211delCT, p.Leu404fsX12; c.1459C>T, p.Arg487X; c.1489dupC, p.Arg497fsX6). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 277064 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae RCV001062982 SCV001227809 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-02-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr157Leufs*15) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of Lynch Syndrome in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 491710). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.

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