Submissions for variant NM_000251.3(MSH2):c.2388del (p.Val797fs)

dbSNP: rs63749983

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076465	SCV000107494	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000219933	SCV000275131	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The c.2388delT pathogenic mutation, located in coding exon 14 of the MSH2 gene, results from a deletion of one nucleotide at position 2388, causing a translational frameshift with a predicted alternate stop codon (p.V797Lfs*15). This alteration has been reported in the literature in 1 of 101 unrelated patients affected by colorectal cancer or an HNPCC-associated cancer (endometrium, small bowel, urinary tract); authors suggest that this mutation may be specific for Polish families as it had not been previously described at the time of publication (Kurzawski G et al, J. Med. Genet. 2002 Oct; 39(10):E65). A detailed clinical case study on a woman with this exact mutation and multiple primary tumors (7) suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up (Janavicius R et al, Hered Cancer Clin Pract 2012 ; 10(1):1). This alteration has also been reported in a female diagnosed with MMR deficient colorectal cancer at age 30 and having a family history of HNPCC-associated cancers (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). 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	RCV002514353	SCV003524610	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val797Leufs*15) 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: 12362047). ClinVar contains an entry for this variant (Variation ID: 90963). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452909	SCV004186851	pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000584065	SCV000691911	pathogenic	not provided		no assertion criteria provided	clinical testing