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

Total submissions: 8

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 colon cancer	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.