Submissions for variant NM_000251.3(MSH2):c.643C>T (p.Gln215Ter)

dbSNP: rs63751274

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076658	SCV000107693	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000657646	SCV000779392	pathogenic	not provided	2016-12-30	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.643C>T at the cDNA level and p.Gln215Ter (Q215X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one family with a history suggestive of Lynch syndrome (Bapat 1999), and is considered pathogenic.
Invitae	RCV001854334	SCV002233209	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-06-27	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: 91154). This premature translational stop signal has been observed in individual(s) with colorectal cancer and ovarian cancer (PMID: 10190329, 30322717). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln215*) 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).
Ambry Genetics	RCV002362713	SCV002656780	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-16	criteria provided, single submitter	clinical testing	The p.Q215* variant (also known as c.643C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 643. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been reported in a patient diagnosed with a MSI-H early-onset colon cancer whose family history meets Amsterdam II criteria, as well as, in a patient diagnosed with a mismatch repair-deficient (MMRd) colorectal cancer and in a MMRd endometrial tumor cell line (Boyer JC et al. Cancer Res., 1995 Dec;55:6063-70; Bapat BV et al. Hum. Genet., 1999 Feb;104:167-76; Baert-Desurmont S et al. Eur. J. Hum. Genet., 2018 11;26:1597-1602). 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.
Human Genetics Bochum, Ruhr University Bochum	RCV002463636	SCV002758604	pathogenic	Lynch syndrome 1	2022-02-10	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PS4, PM2
Johns Hopkins Genomics, Johns Hopkins University	RCV003150809	SCV003839083	pathogenic	Mismatch repair cancer syndrome 2	2023-01-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002463636	SCV004188993	pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.