Submissions for variant NM_000251.3(MSH2):c.1222dup (p.Tyr408fs)

dbSNP: rs63751142

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076069	SCV000107084	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
GeneDx	RCV000479156	SCV000568627	pathogenic	not provided	2016-12-22	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH2 is denoted c.1222dupT at the cDNA level and p.Tyr408LeufsX9 (Y408LfsX9) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ACTC[dupT]ATCA. The duplication causes a frameshift which changes a Tyrosine to a Leucine at codon 408, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.1222dupT has been reported in association with Lynch syndrome (Casey 2005). We consider this variant to be pathogenic.
Ambry Genetics	RCV000491975	SCV000580539	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	clinical testing	The c.1222dupT pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from a duplication of T at nucleotide position 1222, causing a translational frameshift with a predicted alternate stop codon (p.Y408Lfs*9). This mutation has been reported in several individuals and families suspected of Lynch syndrome based on personal and/or family history. The tumors of multiple probands have demonstrated high microsatellite instability and/or loss of MSH2 expression on IHC (Casey G et al. JAMA. 2005 Feb;293:799-809; Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702; Mueller-Koch Y et al. Gut. 2005 Dec;54:1733-40; Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117:269-77). Of note, this alteration is also designated as 1222insT, 1223insT, and 1222_1223inT in published literature. 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	RCV000629830	SCV000750786	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-09-16	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: 90573). This variant is also known as c.1223insT, c.1222_1223insT. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 15713769, 15849733, 15926618, 15955785). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr408Leufs*9) 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).
CeGaT Center for Human Genetics Tuebingen	RCV000479156	SCV001334860	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452811	SCV004188049	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353606	SCV000592493	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Tyr408LeufsX9 variant was identified in 7 of 4808 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome (Casey 2005, Holinski-Feder 2001, Mangold 2005, Mueller-Koch 2005, Parc 2003, Wolf 2005). Tumour samples from two of these probands showed loss of MSH2 protein expression, and additional testing of one tumour showed high microsatellite instability (Casey 2005, Mueller-Koch 2005). The variant was also identified in dbSNP (ID: rs63751142), HGMD, UMD (14X as a causal variant), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, and the ClinVar Database (classified as pathogenic by InSiGHT). The p.Tyr408LeufsX9 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 408 and leads to a premature stop codon 9 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.