Submissions for variant NM_000251.3(MSH2):c.859G>T (p.Gly287Ter)

dbSNP: rs63750276

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076737	SCV000107774	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000115545	SCV000149454	pathogenic	not provided	2014-02-28	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.859G>T at the cDNA level and p.Gly287Ter (G287X) at the protein level. The substitution creates a nonsense variant, changing a Glycine to a premature stop codon (GGA>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with hereditary colorectal cancer (Rahner 2007). We therefore consider this variant to be pathogenic.
Invitae	RCV001053401	SCV001217659	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly287*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91232). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 17653898, 26681312). This variant is not present in population databases (ExAC no frequency).
Ambry Genetics	RCV002444540	SCV002676283	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-25	criteria provided, single submitter	clinical testing	The p.G287* pathogenic mutation (also known as c.859G>T), located in coding exon 5 of the MSH2 gene, results from a G to T substitution at nucleotide position 859. This changes the amino acid from a glycine to a stop codon within coding exon 5. This mutation has been reported as germline in individuals with colorectal cancer including at least one whose tumor demonstrated loss of MSH2 and MSH6 protein expression by IHC (Rahner N et al. Acta Oncol, 2007;46:763-9; Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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.	RCV003452969	SCV004186934	pathogenic	Lynch syndrome 1	2023-07-28	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.