ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.503dup (p.Asn168fs) (rs63749959)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677883 SCV000804044 pathogenic Carcinoma of colon 2018-03-19 no assertion criteria provided clinical testing
GeneDx RCV000583950 SCV000211076 pathogenic not provided 2014-03-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.503dupA at the cDNA level and p.Asn168LysfsX4 (N168KfsX4) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TAAAAA[A]TCCA. The duplication causes a frameshift, which changes an Asparagine to a Lysine at codon 168, and creates a premature stop codon at position 4 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 503dupA has been reported in association with Lynch syndrome by Dominguez-Valentin et al. (2013) and is considered pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075739 SCV000106746 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV000684801 SCV000543603 pathogenic Hereditary nonpolyposis colon cancer 2018-11-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn168Lysfs*4) 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 several individuals with a personal and/or family history of Lynch Syndrome (PMID: 12658575, 24344984, 15849733, 15713769, 17054581). This variant is also known as 168insA, c.503_504insA, and c.503_4insA in the literature. ClinVar contains an entry for this variant (Variation ID: 90250). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000583950 SCV000691848 pathogenic not provided no assertion criteria provided clinical testing
PreventionGenetics RCV000583950 SCV000805972 pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing

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