ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3991C>T (p.Arg1331Ter)

dbSNP: rs267608094
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000035325 SCV000108181 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon (variant causes splicing aberration)
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000035325 SCV000058973 pathogenic Lynch syndrome 2019-04-19 criteria provided, single submitter clinical testing The p.Arg1331X variant in MSH6 has been reported in the heterozygous state in 6 individuals with MSH6-associated cancers (Stormorken 2005, Sjursen 2010, Bonadona 2011, Susswein 2015, LMM data). This variant has also been reported in 2 individuals with clinical features of constitutional mismatch repair syndrome in the compound heterozygous state with another MSH6 variant (Plaschke 2006) or in the homozygous state (Lavoine 2015). In addition, The p.Arg1331X variant has been identified in 1/30646 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1331. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Studies have demonstrated that the variant results in skipping of exon 9, giving rise to a truncated mRNA leading to drastically reduced MSH6 protein levels, suggesting that this truncated protein is unstable (Plaschke 2006). Moreover, the p.Arg1331X variant has been classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108181.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PVS1_Strong, PM3_Supporting.
Ambry Genetics RCV000131743 SCV000186784 pathogenic Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing The p.R1331* pathogenic mutation (also known as c.3991C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at nucleotide position 3991. This changes the amino acid from an arginine to a stop codon within coding exon 9. <span style="background-color:initial">This mutation has been reported in multiple individuals with Lynch syndrome<span style="background-color:initial"> <span style="background-color:initial">(Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6<span style="background-color:initial">; Sjursen W et al. J. Med. Genet.<span style="background-color:initial"> 2010 Sep;47:579-85; <span style="background-color:initial">van Lier MG et al. J. Pathol.<span style="background-color:initial"> 2012 Apr;226:764-74), including at least one with breast cancer (Roberts ME et al. Genet. Med. 2018 10;20:1167-1174). This mutation has also been reported in the homozygous state in an individual with constitutional mismatch repair deficiency who was diagnosed with multiple caf&eacute;-au-lait​ macules and colorectal cancer at age 11 (Lavoine N et al. Med. Genet. 2015 Nov;52:770-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000202305 SCV000211329 pathogenic not provided 2022-08-11 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost, and also demonstrated to cause skipping of exon 9 in a portion of transcripts (Plaschke 2006); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Stormorken 2005, Sjursen 2010, van Lier 2012, Goodfellow 2015, Usha 2016, Tian 2019); Observed in the homozygous or compound heterozygous state in individuals with personal history and/or IHC results consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (Plaschke 2006, Lavoine 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24989436, 25525159, 20587412, 18409202, 18709565, 26681312, 26552419, 26318770, 12019211, 22081473, 16034045, 21056691, 21674763, 21376568, 18301448, 27380347, 21642682, 16418736, 27601186, 24362816, 19851887, 30322717, 31447099, 32019277, 31054147, 21120944, 17531815, 33087929, 34445333, 32427313, 30787465)
Invitae RCV000524203 SCV000283835 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1331*) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16034045, 18301448, 20587412, 21056691, 21642682, 27601186). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 42472). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MSH6 function (PMID: 16418736). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000410467 SCV000488239 pathogenic Colorectal cancer, hereditary nonpolyposis, type 5 2016-02-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202305 SCV000601596 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824584 SCV000695906 pathogenic Hereditary nonpolyposis colon cancer 2022-01-26 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3991C>T (p.Arg1331X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245746 control chromosomes (gnomAD). c.3991C>T has been reported in the literature in individuals affected with varying cancer phenotypes including colorectal (Sjursen_2010, Limburg_2011, van Lier_2012, Lavoine_2015), endometrial (Goodfellow_2015), and breast (Susswein_2016), and in individuals with a family history of Lynch syndrome (Plaschke_2006). These data indicate that the variant is very likely to be associated with disease. The variant has, however, also been reported in seemingly healthy individuals, including the father of a compound heterozygote child with Lynch Syndrome, indicating that it may exhibit reduced penetrance (Plaschke_2006). One publication reports experimental evidence indicating that the variant results in exon 9 skipping (Plaschke_2006), and multiple publications report a reduction of IHC staining for MSH6 protein in samples from individuals with this variant. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Health, Inc RCV000131743 SCV001340973 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 9 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/245746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000410467 SCV001429321 pathogenic Colorectal cancer, hereditary nonpolyposis, type 5 2019-02-08 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000410467 SCV001434868 pathogenic Colorectal cancer, hereditary nonpolyposis, type 5 2018-10-14 criteria provided, single submitter clinical testing The c.3991C>T (p.Arg1331*) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome-associated tumors and loss of MSH6 expression through immunohistochemistry staining were identified in the tumors of these individuals (PMID 16034045,18301448, 20587412). This variant has also been reported in two individuals with constitutional mismatch repair syndrome. One the two individuals carry this variant in trans with a likely pathogenic MSH6 variant (p.Arg1076Cys, PMID 16418736) and the other individual was homozygous with this variant (PMID 26318770). This variant is extremely rare in general population databases. Therefore, this c.3991C>T (p.Arg1331*) variant in the MSH6 gene is classified as pathogenic.
Mayo Clinic Laboratories,Mayo Clinic RCV000202305 SCV000257292 likely pathogenic not provided no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000202305 SCV001744264 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000202305 SCV001952768 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000202305 SCV001969250 pathogenic not provided no assertion criteria provided clinical testing

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