Submissions for variant NM_000251.3(MSH2):c.1221_1222del (p.Tyr408fs)

dbSNP: rs587779076

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076068	SCV000107081	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
Ambry Genetics	RCV000491679	SCV000580435	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The c.1221_1222delCT pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1221 to 1222, causing a translational frameshift with a predicted alternate stop codon (p.Y408Sfs*8). This mutation has been reported in an individual diagnosed with colon cancer at age 26 whose tumor showed high microsatellite instability and absent MSH2 and MSH6 staining on IHC (van Puijenbroek M et al. Fam Cancer. 2008;7(4):319-30). 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	RCV000076068	SCV000696200	pathogenic	Lynch syndrome	2017-03-03	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1221_1222delCT (p.Tyr408Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 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 (e.g. c.1576delA, p.Thr526fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121304 control chromosomes. Multiple reputable databases classified this variant as pathogenic including InSIGHT and UMD. In addition, this variant is located in the DNA mismatch repair protein MutS, core domain (InterPro). The variant of interest has not, to our knowledge, been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as pathogenic.
Invitae	RCV001049389	SCV001213435	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-09	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: 90572). This premature translational stop signal has been observed in individual(s) with MSH2-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr408Serfs*8) 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).
Color Diagnostics, LLC DBA Color Health	RCV000491679	SCV001735422	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-12	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with Lynch syndrome-associated cancers (PMID: 18415027, 18566915, 29967336). 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.
Myriad Genetics, Inc.	RCV003452810	SCV004188999	pathogenic	Lynch syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.