Submissions for variant NM_000251.3(MSH2):c.2588dup (p.Tyr863Ter)

dbSNP: rs1553370435

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657824	SCV000779580	likely pathogenic	not provided	2017-06-23	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted MSH2 c.2588dupA at the cDNA level and p.Tyr863Ter (Y863X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GGAT[dupA]TGAT. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene includes the Helix-turn-helix domain and a region that interacts with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). Based on currently available evidence, we consider this variant to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809827	SCV000950006	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2018-10-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 546053). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr863*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV001016027	SCV001176933	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-25	criteria provided, single submitter	clinical testing	The c.2588dupA pathogenic mutation, located in coding exon 15 of the MSH2 gene, results from a duplication of A at nucleotide position 2588, causing a translational frameshift with a predicted alternate stop codon (p.Y863*). 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.	RCV003451614	SCV004186823	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.