Submissions for variant NM_000251.3(MSH2):c.2579C>A (p.Ser860Ter)

dbSNP: rs63750849

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076507	SCV000107536	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV002228186	SCV000548310	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-01-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12655562, 15849733). ClinVar contains an entry for this variant (Variation ID: 91005). This sequence change creates a premature translational stop signal (p.Ser860*) 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	RCV000491600	SCV000580644	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.S860* pathogenic mutation (also known as c.2579C>A), located in coding exon 15 of the MSH2 gene, results from a C to A substitution at nucleotide position 2579. This changes the amino acid from a serine to a stop codon within coding exon 15. This mutation has been reported in multiple HNPCC/Lynch syndrome families to date (Krüger S et al. Hum. Mutat., 2003 Apr;21:445-6 and Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281910	SCV002572159	pathogenic	Hereditary nonpolyposis colon cancer	2022-08-19	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2579C>A (p.Ser860X) 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. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 251426 control chromosomes (gnomAD). c.2579C>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome (e.g. Kruger_2003, Mangold_2005, Yang_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact of the variant on protein function has been reported; however at least one functional study has shown that deletion of the 60 C-terminal amino acids from MSH2, a region which would also be truncated as a result of this variant, severely affects the stability of MSH2/MSH6 heterodimer and strongly attenuates DNA mismatch repair (e.g. Wielders_2017). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000144616	SCV004186995	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.
Pathway Genomics	RCV000144616	SCV000189943	pathogenic	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing