Submissions for variant NM_000251.3(MSH2):c.2563C>T (p.Gln855Ter)

dbSNP: rs1553370404

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526846	SCV000625385	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln855*) 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). ClinVar contains an entry for this variant (Variation ID: 455569). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch Syndrome (PMID: 17939062, 25559809, 31588121). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV002431520	SCV002741668	pathogenic	Hereditary cancer-predisposing syndrome	2018-08-23	criteria provided, single submitter	clinical testing	The p.Q855* pathogenic mutation (also known as c.2563C>T), located in coding exon 15 of the MSH2 gene, results from a C to T substitution at nucleotide position 2563. This mutation, designated p.Gln855X, was reported in an HNPCC family with multiple individuals affected with urinary tract cancers (Geary J et al. Fam. Cancer, 2008 Oct;7:163-72). This mutation was also identified in a patient with a personal and family history of early onset colorectal cancer (Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32). This changes the amino acid from a glutamine to a stop codon within coding exon 15. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320673	SCV004024767	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003449540	SCV004186803	pathogenic	Lynch syndrome 1	2023-08-09	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.