ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3991C>T (p.Arg1331Ter) (rs267608094)

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Total submissions: 12
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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,Partners HealthCare 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 2018-04-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.3991C>T at the cDNA level and p.Arg1331Ter (R1331X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). MSH6 Arg1331Ter results in the loss of 30 amino acids at the end of the protein. Although nonsense-mediated decay is not expected to occur, RT-PCR analysis and sequencing have found this variant to result in partial skipping of exon 9 (Plaschke 2006). This variant has been reported in several individuals with endometrial, colorectal, and other Lynch syndrome-related cancers, with studied tumors demonstrating loss of MSH6 expression on immunohistochemistry (IHC) analysis (Stormorken 2005, Sjursen 2010, van Lier 2012, Usha 2016). MSH6 Arg1331Ter was also observed in the compound heterozygous state with MSH6 Arg1076Cys in an individual with personal history and IHC results consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (Plaschke 2006) and is classified as pathogenic by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT, Thompson 2014). Based on current evidence, we consider this variant to be pathogenic.
Invitae RCV000524203 SCV000283835 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the penultimate exon of the MSH6 mRNA at codon 1331 (p.Arg1331*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 30 amino acids of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with rectal, endometrial, breast, colon, and brain cancer (PMID: 21642682, 18301448, 16034045, 21056691, 20587412, 27601186). In addition, this variant has been reported in two individuals with autosomal recessive constitutional mismatch repair deficiency syndrome. One of these individuals was homozygous for this variant and the other had this variant in trans with a pathogenic MSH6 missense variant (PMID: 26318770, 16418736). ClinVar contains an entry for this variant (Variation ID: 42472). Experimental studies have shown that this nonsense change results in partial skipping of exon 9, creating a stop signal in the final exon and giving rise to a truncated mRNA transcript and an unstable MSH6 protein (PMID: 16418736). A different truncation that disrupts the final 31 amino acids of the protein (p.Leu1330Valfs*12) has been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that disruption of this region of the MSH6 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000410467 SCV000488239 pathogenic Hereditary nonpolyposis colorectal cancer 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 RCV000035325 SCV000695906 pathogenic Lynch syndrome 2019-06-25 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
Institute of Human Genetics, University of Leipzig Medical Center RCV000410467 SCV001429321 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2019-02-08 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000410467 SCV001434868 pathogenic Hereditary nonpolyposis colorectal cancer 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

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