ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1246A>T (p.Lys416Ter) (rs267607823)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205488 SCV000260324 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 416 (p.Lys416*). It is expected to result in an absent or disrupted protein product. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in an individual with endometrial cancer diagnosed at age 40 with a family history that meets Amsterdam II criteria for Lynch Syndrome (PMID: 20034658). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000481776 SCV000569498 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1246A>T at the cDNA level and p.Lys416Ter (K416X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least two individuals meeting Amsterdam II criteria (Walsh 2010, Dudley 2015) and is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481776 SCV000601348 pathogenic not provided 2017-01-13 criteria provided, single submitter clinical testing
Counsyl RCV000576496 SCV000677831 pathogenic Lynch syndrome II 2017-02-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV001010534 SCV001170750 pathogenic Hereditary cancer-predisposing syndrome 2019-07-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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