Submissions for variant NM_000251.3(MSH2):c.650_654del (p.Ile217fs)

dbSNP: rs63751602

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076676	SCV000107711	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000492017	SCV000580639	pathogenic	Hereditary cancer-predisposing syndrome	2018-08-10	criteria provided, single submitter	clinical testing	The c.650_654delTTCAA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of 5 nucleotides at nucleotide positions 650 to 654, causing a translational frameshift with a predicted alternate stop codon (p.I217Kfs*13). This mutation was reported in a 28-year-old Japanese woman diagnosed with MSI-H descending colon cancer (Ishida H et al. Jpn. J. Clin. Oncol. 2002 Jul;32:266-9). 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.
Invitae	RCV001214810	SCV001386515	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-20	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: 91172). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 12324578). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile217Lysfs*13) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323386	SCV004030118	pathogenic	Hereditary nonpolyposis colon cancer	2023-07-05	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.650_654delTTCAA (p.Ile217LysfsX13) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 249738 control chromosomes (gnomAD). c.650_654delTTCAA has been reported in the literature in an individual affected with colorectal cancer with microsatellite instability (Ishida_2002). These data suggest the variant is likely associated with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.