ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1975C>T (p.Arg659Ter) (rs63751310)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075444 SCV000106442 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000128869 SCV000172726 pathogenic Hereditary cancer-predisposing syndrome 2018-01-29 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)
GeneDx RCV000202252 SCV000321898 pathogenic not provided 2018-05-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.1975C>T at the cDNA level and p.Arg659Ter (R659X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). In addition, MLH1 Arg659Ter has also been reported to result in skipping of exon 17 (Nystr?m-Lahti 1999, Casey 2005). Both MLH1 Arg659Ter and skipping of exon 17 are predicted to cause loss of normal protein function, through protein truncation or nonsense-mediated mRNA decay, or resulting in an abnormal protein product, respectively. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). This variant has been reported in multiple individuals with personal and/or family histories suggestive of Lynch syndrome (Nystr?m-Lahti 1996 , Holmberg 1998, Casey 2005, Choi 2009, Nilbert 2009, Rajender 2010, Carneiro da Silva 2015). In a GST-fusion assay, this variant was shown to cause defective PMS2 interaction (Kondo 2003). Based on currently available evidence, we consider MLH1 Arg659Ter to be pathogenic.
Invitae RCV000524261 SCV000543616 pathogenic Hereditary nonpolyposis colon cancer 2018-04-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg659*) 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 the literature in individuals affected with Lynch syndrome (PMID: 8776590, 10534773, 24344984, 15713769, 19698169, 26437257, 18561205) and has been shown to segregate with disease in one family (PMID: 20167975). ClinVar contains an entry for this variant (Variation ID: 89962). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075444 SCV000592431 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202252 SCV000889395 pathogenic not provided 2015-09-24 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075444 SCV000914324 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202252 SCV000257077 pathogenic not provided no assertion criteria provided research

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