Submissions for variant NM_000179.2(MSH6):c.3436C>T (p.Gln1146Ter) (rs63750356)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074849	SCV000108061	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000561009	SCV000673950	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-24	criteria provided, single submitter	clinical testing	The p.Q1146* pathogenic mutation (also known as c.3436C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3436. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This pathogenic mutation was reported in an individual with personal and family history consistent with Muir-Torre syndrome (Mangold E et al. Br. J. Dermatol. 2007 Jan;156(1):158-62). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000629768	SCV000750724	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2017-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1146*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 17199584). ClinVar contains an entry for this variant (Variation ID: 89382). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657654	SCV000779402	pathogenic	not provided	2017-06-14	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3436C>T at the cDNA level and p.Gln1146Ter (Q1146X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), 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 at least two individuals with colorectal cancer, one of whom also had a sebaceous neoplasm, and is considered pathogenic (Mangold 2007, Steinke 2008).