ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4001G>A (p.Arg1334Gln) (rs267608122)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491705 SCV000580100 pathogenic Hereditary cancer-predisposing syndrome 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification,Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Color RCV000491705 SCV000690430 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Counsyl RCV000576708 SCV000677749 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000160701 SCV000211330 pathogenic not provided 2019-03-05 criteria provided, single submitter clinical testing This variant is predicted to disrupt a natural splice site and cause abnormal splicing. Although the nucleotide substitution results in the change of an Arginine to a Glutamine at codon 1334, and is called Arg1334Gln in the literature, we are using onlythe nucleotide nomenclature to refer to the variant since the defect is likely to be one of splicing rather than a resultingmissense variant. The variant was observed in multiple individuals with tumor histology and personal and/orfamily histories consistent with Lynch syndrome, segregating with disease in multiple kindreds (Wijnen1999, Hendriks2003, Overbeek 2007, Van Puijenbroek 2008, You 2010, Klarskov 2011, Lagerstedt-Robinson 2016). The InternationalSociety for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based ontheir multifactorial likelihood model (Thompson 2014). This variant was not observed in large population cohorts (Lek2016).
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074974 SCV000108190 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000542786 SCV000624960 pathogenic Hereditary nonpolyposis colon cancer 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1334 of the MSH6 protein (p.Arg1334Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 9 of the MSH6 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in two Lynch syndrome (LS) families (PMID: 10508506, 15236168, 21836479) and has been reported in other unrelated individuals affected with LS-associated cancers (PMID: 21081928, 17453009, 26681312). ClinVar contains an entry for this variant (Variation ID: 89506). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000074974 SCV000711435 pathogenic Lynch syndrome 2018-06-15 criteria provided, single submitter clinical testing The p.Arg1334Gln variant in MSH6 has been reported in 4 individuals with MSH6-as sociated cancers and segregated with disease in 7 affected relatives from 2 fami lies (Hendriks 2004, Overbeek 2007, van Puijenbroek 2008, Klarskov 2011). It was absent from large population studies. This variant affects the last base of the exon, which is part of the 5? splice region and computational tools predict alt ered splicing, which is expected to lead to an altered or absent protein. Consis tent with this, tumors from patients harboring this variant showed absence of MS H6 protein (Hendriks 2004, Klarskov 2011). This variant was classified as Pathog enic on Sept 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV00 0108190.2). In summary, this variant meets criteria to be classified as pathogen ic for Lynch syndrome. ACMG/AMP criteria applied: PP1_Str, PS4_Mod, PM2, PS3_Mod , PP3 (Richards 2015).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202090 SCV000257296 uncertain significance not specified no assertion criteria provided research

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