ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2070_2071insTT (p.Ile691Leufs) (rs876659681)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221270 SCV000276394 pathogenic Hereditary cancer-predisposing syndrome 2016-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Center for Human Genetics, Inc RCV000659877 SCV000781764 likely pathogenic Lynch syndrome II 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000543770 SCV000625120 pathogenic Hereditary nonpolyposis colon cancer 2018-01-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MLH1 gene (p.Ile691Leufs*93). While this is not anticipated to result in nonsense mediated decay, it is expected to replace the last 66 amino acids of the MLH1 protein with 93 random amino acids, creating a new downstream translational stop signal in the last exon that extends the length of the protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 232298). This truncation affects the highly conserved C-terminal domain responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Different truncating variants downstream of this variant (including p.Ser726*, p.Lys732* and p.Tyr750*) have been reported in individuals affected with Lynch syndrome and have been determined to be pathogenic (PMID: 10923051, 25197397, 10422993, Invitae). This suggests that disruption of this region of the MLH1 protein is causative of disease. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508512 SCV000601386 likely pathogenic not provided 2016-10-06 criteria provided, single submitter clinical testing

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