Submissions for variant NM_000251.3(MSH2):c.2292G>A (p.Trp764Ter)

dbSNP: rs63751105

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076451	SCV000107481	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Color Diagnostics, LLC DBA Color Health	RCV000584494	SCV000690060	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 15945244, 16736289, 16810763). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV001206689	SCV001378009	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90949). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15945244, 16736289, 16810763). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp764*) 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).
Ambry Genetics	RCV000584494	SCV002734149	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-14	criteria provided, single submitter	clinical testing	The p.W764* pathogenic mutation (also known as c.2292G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2292. This changes the amino acid from a tryptophan to a stop codon within coding exon 14. This mutation, designated as p.W764X, has been reported in patients from various ethnicities who meet Amsterdam criteria (Czakó L et al. Orv Hetil, 2005 May;146:1009-16; Spaepen M et al. Fam Cancer, 2006;5:179-89; Wang XL et al. World J Gastroenterol, 2006 Jul;12:4074-7). A similar alteration (c.2291G>A) resulting in the same premature stop codon (designated p.Trp764X) as been reported in an individual with the Muir-Torre variant of Lynch syndrome whose colorectal cancer and hepatocellular carcinoma both demonstrated high microsatellite instability and MSH2-/MSH6- by IHC (Casper M et al. Scand J Gastroenterol, 2013 Mar;48:344-51). 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.