Submissions for variant NM_000251.3(MSH2):c.2275G>T (p.Gly759Ter)

dbSNP: rs63749854

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076448	SCV000107477	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000223378	SCV000273589	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	The p.G759* pathogenic mutation (also known as c.2275G>T), located in coding exon 14 of the MSH2 gene, results from a G to T substitution at nucleotide position 2275. This changes the amino acid from a glycine to a stop codon within coding exon 14. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2 expression by immunohistochemistry (Stormorken AT et al. J Clin Oncol. 2005 Jul 20;23(21):4705-12; Grindedal EM et al. Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2460-7; Sjursen W et al. J Med Genet. 2010 Sep;47(9):579-85). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798392	SCV000938008	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-06-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly759*) 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 Lynch syndrome and prostrate cancer (PMID: 15342696, 16034045, 19723918, 27601186, 28514183). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 90946). 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.
Myriad Genetics, Inc.	RCV003452903	SCV004187933	pathogenic	Lynch syndrome 1	2023-08-08	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.