Submissions for variant NM_000251.3(MSH2):c.1321dup (p.Thr441fs)

dbSNP: rs63750807

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076125	SCV000107140	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000491560	SCV000580432	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-26	criteria provided, single submitter	clinical testing	The c.1321dupA pathogenic mutation, located in coding exon 8 of the MSH2 gene, results from a duplication of A at nucleotide position 1321, causing a translational frameshift with a predicted alternate stop codon (p.T441Nfs*2). This mutation was detected in an individual diagnosed with MSI-H rectosigmoid colon cancer at age 40 (Barnetson et al. N. Engl. J. Med. 2006;354(26):2751-63). A Korean female diagnosed with ovarian cancer at age 49 and having a family history of stomach and colorectal cancers has also been reported with this mutation (Eoh KJ et al. Cancer Res Treat, 2018 Jul;50:917-925). 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	RCV001854314	SCV002220333	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-12	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: 90629). This variant is also known as c.1320_1321insA. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16807412, 29020732). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr441Asnfs*2) 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).
Myriad Genetics, Inc.	RCV003452822	SCV004186946	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.
CeGaT Center for Human Genetics Tuebingen	RCV003886375	SCV004702547	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH2: PVS1, PM2