Submissions for variant NM_000179.3(MSH6):c.3838C>T (p.Gln1280Ter)

dbSNP: rs63750139

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074940	SCV000108154	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000603416	SCV000743213	pathogenic	Lynch syndrome 5	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000603416	SCV000744303	pathogenic	Lynch syndrome 5	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV001229855	SCV001402315	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89472). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11709755, 26517685). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1280*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).
Ambry Genetics	RCV002362701	SCV002626016	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The p.Q1280* pathogenic mutation (also known as c.3838C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at nucleotide position 3838. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This variant has been reported in patients with histories that are consistent with Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome (Berends MJ et al. Am. J. Hum. Genet. 2002 Jan;70:26-37; Plaschke J et al. J. Clin. Oncol. 2004 Nov;22:4486-94; Kets CM et al. Br. J. Cancer. 2006 Dec;95:1678-82; Jóri B et al. Oncotarget. 2015 Dec;6:41108-22). It has also been reported, in the homozygous state, in a patient with constitutional mismatch repair deficiency (CMMRD) syndrome (Gallon R et al. Hum. Mutat. 2019 05;40:649-655). 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.
Myriad Genetics, Inc.	RCV000603416	SCV004187248	pathogenic	Lynch syndrome 5	2023-08-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000603416	SCV000734222	pathogenic	Lynch syndrome 5		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723643	SCV001957419	pathogenic	not provided		no assertion criteria provided	clinical testing