ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2177_2178CA[1] (p.His727fs) (rs267607898)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075569 SCV000106566 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000164558 SCV000215216 pathogenic Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;Other strong data supporting pathogenic classification;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Structural Evidence
Invitae RCV000524280 SCV000253791 pathogenic Hereditary nonpolyposis colon cancer 2019-11-22 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides in exon 19 of the MLH1 mRNA (c.2179_2182delCACA), causing a frameshift at codon 727 (p.His727Phefs*55). This is expected to disrupt the last 30 amino acids of the MLH1 protein and create a new downstream translational stop signal that extends the length of the protein by 24 amino acids. While this is not anticipated to result in nonsense mediated decay, it is expected to result in a disrupted MLH1 protein. This variant is not present in population databases (rs267607898, ExAC no frequency). This variant has been reported in the literature in individuals and families affected with hereditary non-polyposis colorectal cancer or Lynch syndrome (PMID: 8128251, 8630936, 12810663). It is also known as 726 727 del 4bp in the literature. ClinVar contains an entry for this variant (Variation ID: 90083). In an experimental study using a model organism, this variant was shown to cause loss of mismatch repair function (PMID: 9697702), indicating that the disrupted part of the C-terminal domain is required for normal MLH1 function. Variants located downstream of this variant have been determined to be pathogenic (PMID: 16616355, 10923051, 8646682). This suggests that deletion of this region of the MLH1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202306 SCV000279086 pathogenic not provided 2015-12-01 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in MLH1 is denoted c.2179_2182delCACA at the cDNA level and p.His727PhefsX55 (H727FfsX55) at the protein level. The normal sequence, with the bases that are deleted in braces, is CTCA[CACA]TTCT. The deletion causes a frameshift, which changes a Histidine to a Phenylalanine at codon 727, and creates a premature stop codon at position 55 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 30 amino acids are no longer translated correctly and are replaced with 54 alternate amino acids, which are located in the PMS2/MLH3/PMS1 protein interaction domain (Raevaara 2005). MLH1 c.2179_2182delCACA has been reported as a pathogenic variant in individuals meeting Amsterdam criteria for Lynch syndrome (Papadopoulos 1994, Kondo 2003). Multiple functional assays have demonstrated loss of function in association with this variant, as well as an impact on the interaction with PMS2 (Shimodaira 1998, Kondo 2003). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202306 SCV000889399 pathogenic not provided 2018-05-06 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202306 SCV000257089 pathogenic not provided no assertion criteria provided research

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