Submissions for variant NM_000251.3(MSH2):c.425C>G (p.Ser142Ter)

dbSNP: rs63750910

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076598	SCV000107633	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000519167	SCV000617591	pathogenic	not provided	2017-08-21	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.425C>G at the cDNA level and p.Ser142Ter (S142X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been reported in association with Lynch syndrome (Hampel 2005, Haroldsdottir 2016, Sunga2017) and is considered pathogenic
Ambry Genetics	RCV001022162	SCV001183863	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-29	criteria provided, single submitter	clinical testing	The p.S142* pathogenic mutation (also known as c.425C>G), located in coding exon 3 of the MSH2 gene, results from a C to G substitution at nucleotide position 425. This changes the amino acid from a serine to a stop codon within coding exon 3. This mutation was identified in a patient with MSI-H cancer of the cecum diagnosed at age 38 (Hampel H et al. N. Engl. J. Med., 2005 May;352:1851-60). This mutation has also been reported in Hispanic individuals with suspected Lynch syndrome (Rossi BM et al. BMC Cancer 2017 Sep;17:623; Sunga AY et al. Cancer Genet, 2017 Apr;212-213:1-7). Of note, this alteration is also designated as p.Ser142X and p.Ser142* 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	RCV001071576	SCV001236886	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-06-14	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: 91096). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 14514376, 15872200, 28449805, 28874130). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser142*) 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	RCV001797622	SCV002041516	pathogenic	Hereditary nonpolyposis colon cancer	2021-11-08	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.425C>G (p.Ser142X) 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 251410 control chromosomes (gnomAD). c.425C>G has been reported in the literature in individuals affected with Lynch Syndrome (examples: Hampel_2005, Haraldsdottir_2016, and Sunga_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003452940	SCV004188144	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	RCV001022162	SCV004356597	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 14514376, 15872200, 20223042, 26866578, 28449805, 28874130). 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.