Submissions for variant NM_000179.3(MSH6):c.730C>T (p.Gln244Ter)

dbSNP: rs267608066

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075029	SCV000108250	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000984323	SCV001132520	pathogenic	Lynch syndrome 5	2018-03-13	criteria provided, single submitter	curation
Ambry Genetics	RCV002381377	SCV002669722	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	clinical testing	The p.Q244* pathogenic mutation (also known as c.730C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 730. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration was identified in an individual diagnosed with colon cancer at 33 and the colon tumor showed loss of expression of MSH2 and MSH6 on immunohistochemistry (IHC) (Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92). 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	RCV002513799	SCV003524583	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-25	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: 89560). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 18301448). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln244*) 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).
Revvity Omics, Revvity	RCV003144122	SCV003833032	likely pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000984323	SCV004188298	pathogenic	Lynch syndrome 5	2023-08-10	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.