Submissions for variant NM_000251.3(MSH2):c.652C>T (p.Gln218Ter)

dbSNP: rs587779170

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076677	SCV000107712	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV001025372	SCV001187549	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.Q218* pathogenic mutation (also known as c.652C>T), located in coding exon 4 of the MSH2 gene, results from a C to T substitution at nucleotide position 652. This changes the amino acid from a glutamine to a stop codon within coding exon 4. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264589	SCV001442815	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.652C>T (p.Gln218X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 250302 control chromosomes. To our knowledge, no occurrence of c.652C>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001386603	SCV001586867	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-01-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 91173). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln218*) 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.	RCV003452958	SCV004188145	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.
Color Diagnostics, LLC DBA Color Health	RCV001025372	SCV004356613	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.