Submissions for variant NM_000251.3(MSH2):c.2041C>T (p.Gln681Ter)

dbSNP: rs730881762

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491607	SCV000580521	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-13	criteria provided, single submitter	clinical testing	The p.Q681* pathogenic mutation (also known as c.2041C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2041. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration has been reported in a French cohort of patients suspected of having HPNCC/Lynch syndrome (Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13). This variant has also been identified in a family meeting Amsterdam criteria (Liu Y et al. PLoSOne. 2014 Apr 7;9(4):e94170). 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.
GeneDx	RCV000520788	SCV000617592	pathogenic	not provided	2017-09-22	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2041C>T at the cDNA level and p.Gln681Ter (Q681X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been reported at least one family meeting modified Amsterdam criteria for Lynch syndrome(Parc 2003) and is considered pathogenic
Invitae	RCV000541933	SCV000625340	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-23	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: 428498). This premature translational stop signal has been observed in individual(s) with hereditary non-polyposis colorectal cancer (PMID: 12624141, 24710284). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln681*) 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	RCV000586396	SCV000696227	pathogenic	Lynch syndrome	2016-08-12	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.2041C>T (p.Gln681X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2113delG, p.Val705fsX5; c.2152C>T, p.Gln718X; c.2633_2634delAG, p.Glu878fsX3). One in silico tool predicts a damaging outcome for this variant. The variant has been reported in affected individuals in the literature and is absent in 121330 control chromosomes. Taken together, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003449362	SCV004188089	pathogenic	Lynch syndrome 1	2023-08-07	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.