ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1411_1414delAAGA (rs63751592)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075201 SCV000106193 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000162473 SCV000212840 pathogenic Hereditary cancer-predisposing syndrome 2017-05-03 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)
Invitae RCV000524238 SCV000284019 pathogenic Hereditary nonpolyposis colon cancer 2019-01-05 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 13 of the MLH1 mRNA (c.1411_1414delAAGA), causing a frameshift at codon 471. This creates a premature translational stop signal (p.Lys471Aspfs*19) and 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 the literature in families with Lynch syndrome (also known as hereditary non-polyposis colorectal cancer) (PMID: 8574961, 20587412, 17569143, 15926618, 18389388). This variant is also known as c.1410_1413delAAAG in the literature. ClinVar contains an entry for this variant (Variation ID: 89727). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000481773 SCV000565153 pathogenic not provided 2016-08-17 criteria provided, single submitter clinical testing This deletion of four nucleotides in MLH1 is denoted c.1411_1414delAAGA at the cDNA level and p.Lys471AspfsX19 (K471DfsX19) at the protein level. The normal sequence, with the bases that are deleted in braces, is CAGA[AAGA]GACA. The deletion causes a frameshift which changes a Lysine to an Aspartic Acid at codon 471, and creates a premature stop codon at position 19 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 c.1411_1414delAAGA has been reported in families with a clinical diagnosis of Lynch syndrome, with several described as meeting Amsterdam criteria (Liu 1996, Sjursen 2010, Goldberg 2014). We consider this variant to be pathogenic.

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