ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3103C>T (p.Arg1035Ter) (rs63749999)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074803 SCV000108014 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524153 SCV000260888 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1035*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs63749999, ExAC 0.002%). This variant has been observed in a family affected with endometrial and/or ovarian cancer (PMID: 15236168). It has also been reported in an individual affected with endometrial cancer with a family history consistent with Lynch syndrome (PMID: 15483016), and in individuals with ovarian cancer (PMID: 22006311, 23047549). ClinVar contains an entry for this variant (Variation ID: 89338). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000223452 SCV000273005 pathogenic Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000484829 SCV000568723 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3103C>T at the cDNA level and p.Arg1035Ter (R1035X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals with a personal and family history of Lynch syndrome-associated tumors, several of which showed absence of MSH6 protein on immunohistochemistry and/or microsatellite instability (Planck 1999, Hendriks 2004, Plaschke 2004, Walsh 2011, Everett 2014, Kidambi 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484829 SCV000601559 pathogenic not provided 2017-06-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763496 SCV000894282 pathogenic Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000223452 SCV000904986 pathogenic Hereditary cancer-predisposing syndrome 2015-02-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194362 SCV001363850 pathogenic Hereditary nonpolyposis colon cancer 2019-09-16 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3103C>T (p.Arg1035X) 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 1.2e-05 in 247790 control chromosomes (gnomAD). c.3103C>T has been reported in the literature in multiple individuals with personal and family history of HNPCC-associated tumors (most commonly endometrial and/or ovarian cancer) and with loss of MSH6 protein expression and microsatellite instability identified in tumor samples (e.g. Devlin_2008, Hendriks_2004, Pal_2012, Planck_1999, Plasche_2004). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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