Submissions for variant NM_000251.3(MSH2):c.1801C>T (p.Gln601Ter)

dbSNP: rs63750047

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076290	SCV000107311	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000428558	SCV000515989	pathogenic	not provided	2017-07-28	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1801C>T at the cDNA level and p.Gln601Ter (Q601X) 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 observed in an individual with early onset colorectal cancer, whose tumor studies demonstrated microsatellite instability (Farrington 1998). Additionally, this variant has been reported in a family with Muir-Torre syndrome and is considered pathogenic (Kolodner 1994).
Ambry Genetics	RCV000491732	SCV000580481	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The p.Q601* pathogenic mutation (also known as c.1801C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1801. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has previously been reported in multiple individuals diagnosed with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Kolodner RD et al. Genomics 1994 Dec;24(3):516-26; Liu B et al. Nat. Med. 1995 Apr;1(4):348-52; Farrington SM et al. Am J Hum Genet. 1998;63:749-759; Chubb D et al. Nat Communications. 2016 June;7:11883). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000428558	SCV000601441	pathogenic	not provided	2016-01-27	criteria provided, single submitter	clinical testing
Invitae	RCV000809096	SCV000949236	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln601*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 7585065, 7713503). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Q600Ter. ClinVar contains an entry for this variant (Variation ID: 1758). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003450612	SCV004187927	pathogenic	Lynch syndrome 1	2023-08-03	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.
Baylor Genetics	RCV003450612	SCV004196869	pathogenic	Lynch syndrome 1	2023-02-07	criteria provided, single submitter	clinical testing
OMIM	RCV000001828	SCV000021984	pathogenic	Muir-Torré syndrome	1994-12-01	no assertion criteria provided	literature only