ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4001G>A (p.Arg1334Gln) (rs267608122)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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).
Ambry Genetics RCV000491705 SCV000580100 pathogenic Hereditary cancer-predisposing syndrome 2018-12-14 criteria provided, single submitter clinical testing The c.4001G>A pathogenic mutation (also known as p.R1334Q), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 4001. The amino acid change results in arginine to glutamine at codon 1334, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in multiple Lynch syndrome patients and families (Wijnen J et al. Nat Genet. 1999;23(2):142-144; Gille et al. Br J Cancer. 2002;87(8):892-897; Overbeek LI et al. Br J Cancer. 2007;96(10):1605-1612; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at []). Functional studies have also demonstrated the pathogenicity of this variant (Houlleberghs H​ et al. PLoS Genet. 2017 May;13(5):e1006765). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000542786 SCV000624960 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-07 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.
Counsyl RCV000576708 SCV000677749 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-03-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491705 SCV000690430 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing
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 Laboratories, Mayo Clinic RCV000202090 SCV000257296 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355904 SCV001550922 likely pathogenic Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 p.Arg1334Gln variant was identified in 5 of 3358 proband chromosomes (frequency: 0.001) from Dutch, Danish and Norwegian individuals or families with HNPCC (Wijnen_1999_10508506, Nilbert_2009_18566915, Gille_2002_12373605 , Hendriks_2004_15236168, Overbeek_2007_17453009). A bioinformatics tool, CoDP (Combination of the Different Properties), that integrates the prediction results of three methods, namely MAPP, PolyPhen-2 and SIFT and two other structural properties, found the variant had no impact on the MSH6 protein (Terui_2013_23621914). The variant was also identified in dbSNP (ID: rs267608122) “With Likely pathogenic,Pathogenic allele”, ClinVar (classified as pathogenic, reviewed by an expert panel(2013); submitters: pathogenic by InSIGHT and Ambry Genetics, likely pathogenic by GeneDx and uncertain significance by Mayo Clinic Genetic Testing Laboratories), Clinvitae (4x), Cosmic (1x in a glioma), UMD-LSDB (4x as causal), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (9x). The variant was not identified in GeneInsight-COGR, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Arg1334 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Gln to the protein; this information is not very predictive of pathogenicity. The p.Arg1334Gln variant occurs in the last nucleotide of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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