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	2024-07-09	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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch Syndrome (PMID: 17939062, 25559809, 31588121). ClinVar contains an entry for this variant (Variation ID: 455569). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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	2025-03-04	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.