ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1219C>T (p.Gln407Ter) (rs1057517541)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411311 SCV000487919 likely pathogenic Lynch syndrome II 2015-12-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000464749 SCV000592401 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
GeneDx RCV000486818 SCV000571217 pathogenic not provided 2016-08-31 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1219C>T at the cDNA level and p.Gln407Ter (Q407X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>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 one individual with Lynch syndrome (Guindalini 2015) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000464749 SCV000919637 pathogenic Lynch syndrome 2017-09-05 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1219C>T (p.Gln407X) 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.1381A>T, p.Lys461X; 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 121406 control chromosomes. The variant was reported in individuals and families affected by Lynch syndrome (Guindalini 2015, Lagerstedt-Robinson 2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000684819 SCV000543574 pathogenic Hereditary nonpolyposis colon cancer 2018-04-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln407*) 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 reported in an individual affected with sebaceous gland cancer and colorectal cancer (PMID: 26248088), and in individuals affected with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 371799). 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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