ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.156delA (p.Glu53Argfs) (rs63750028)

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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 RCV000213962 SCV000276778 pathogenic Hereditary cancer-predisposing syndrome 2017-03-10 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)
Integrated Genetics/Laboratory Corporation of America RCV000075267 SCV000696118 likely pathogenic Lynch syndrome 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.156delA (p.Glu53Argfs) 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.Leu404fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121360 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075267 SCV000106261 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000533345 SCV000625082 pathogenic Hereditary nonpolyposis colon cancer 2017-02-09 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 2 of the MLH1 mRNA (c.156delA), causing a frameshift at codon 53. This creates a premature translational stop signal (p.Glu53Argfs*4) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic. This particular variant has been reported in an individual with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome in the Leiden Open-source Variation Database (PMID: 21520333). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000582660 SCV000691841 likely pathogenic not provided no assertion criteria provided clinical testing

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