Submissions for variant NM_000251.3(MSH2):c.2432T>G (p.Leu811Ter)

dbSNP: rs63751018

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076473	SCV000107503	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV001388595	SCV001589649	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-09-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu811*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. 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 been observed in individual(s) with Lynch syndrome (PMID: 8581513). ClinVar contains an entry for this variant (Variation ID: 90971). This variant is not present in population databases (ExAC no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298462	SCV002598592	pathogenic	Hereditary nonpolyposis colon cancer	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2432T>G (p.Leu811X) 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 251338 control chromosomes (gnomAD). c.2432T>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and Lynch syndrome (examples: Miyaki_1995, Lu_1996, and Domingo_2004). These data indicate that the variant is associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003452910	SCV004187834	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.