Submissions for variant NM_000251.3(MSH2):c.610G>T (p.Gly204Ter)

dbSNP: rs63750574

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076653	SCV000107688	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000815594	SCV000956055	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly204*) 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 (PMID: 15309712, 23640085). ClinVar contains an entry for this variant (Variation ID: 91149). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307390	SCV002600736	pathogenic	Hereditary nonpolyposis colon cancer	2022-10-27	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.610G>T (p.Gly204X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251056 control chromosomes (gnomAD). c.610G>T has been reported in the literature in multiple individuals affected with Lynch Syndrome, gastric cancer, endometrial cancer, and breast cancer with evidence of co-segregation in multiple family members (Zhang_2021, Liu_2004, Sheng_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV003162499	SCV003870558	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	The p.G204* pathogenic mutation (also known as c.610G>T), located in coding exon 3 of the MSH2 gene, results from a G to T substitution at nucleotide position 610. This changes the amino acid from a glycine to a stop codon within coding exon 3. This mutation has been reported in families meeting Amsterdam criteria and/or with MSI-H tumors demonstrating loss of MSH2 expression by IHC (Liu SR et al. World J Gastroenterol, 2004 Sep;10:2647-51; Sheng JQ et al. Chin J Dig Dis, 2006;7:197-205; Zhang YJ et al. Gastroenterol Rep (Oxf), 2021 Aug;9:339-349). 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.	RCV003452955	SCV004188135	pathogenic	Lynch syndrome 1	2023-07-27	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.