ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3991C>T (p.Arg1331Ter) (rs267608094)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131743 SCV000186784 pathogenic Hereditary cancer-predisposing syndrome 2017-06-21 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)
Counsyl RCV000410467 SCV000488239 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-02-02 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000035325 SCV000695906 pathogenic Lynch syndrome 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3991C>T (p.Arg1331X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 114870 control chromosomes (ExAC). Multiple publications have reported the variant in affected individuals with varying phenotypes: Lynch syndrome, breast, colon, rectal, and endometrial cancers, along with multiple compound heterozygote and homozygote individuals presenting with early onset of HNPCC-associated cancers. Along with, a father of a compound heterozygote affected individual, who carries the variant and is indicated to be healthy and older than the average age of onset and UMD cites the variant to be observed in two asymptomatic carriers. Hence, suggesting reduced penetrance. A functional study, Plaschke_2006, indicates the variant causes exon 9 skipping and multiple publications indicate the absence of MSH6 protein expression via IHC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as "pathogenic."
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)
Invitae RCV000524203 SCV000283835 pathogenic Hereditary nonpolyposis colon cancer 2018-06-26 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 reported in the literature 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035325 SCV000058973 pathogenic Lynch syndrome 2017-09-18 criteria provided, single submitter clinical testing The p.Arg1331X variant in MSH6 has been reported in the heterozygous state in 6 individuals with Lynch Syndrome-associated cancers (Stormorken 2005, Sjursen 201 0, Bonadona 2011, Susswein 2015, LMM unpublished data). This variant has also be en reported in 2 individuals with clinical features of constitutional mismatch r epair syndrome in the compound heterozygous state with another MSH6 variant (Pla schke 2006) or in the homozygous state (Lavoine 2015). In addition, The p.Arg133 1X variant has been identified in 1/30646 South Asian chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs2676080 94). This nonsense variant leads to a premature termination codon at position 1 331. This alteration occurs within the terminal 50 bases of the second to last e xon and is more likely to escape nonsense mediated decay (NMD) and result in a t runcated 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 200 6). Heterozygous loss of function of the MSH6 gene is an established disease mec hanism in individuals with Lynch syndrome. Moreover, the p.Arg1331X variant has been classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiG HT Expert Panel (ClinVar SCV000108181.2). In summary, this variant meets criteri a to be classified as pathogenic for Lynch syndrome in an autosomal dominant man ner based upon predicted impact to the protein, reports in multiple affected ind ividuals, very low frequency in controls and functional studies.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202305 SCV000257292 likely pathogenic not provided no assertion criteria provided research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202305 SCV000601596 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing

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