Submissions for variant NM_000251.3(MSH2):c.1835C>G (p.Ser612Ter)

dbSNP: rs63750493

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076300	SCV000107321	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000491040	SCV000580614	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-16	criteria provided, single submitter	clinical testing	The p.S612* pathogenic mutation (also known as c.1835C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1835. This changes the amino acid from a serine to a stop codon within coding exon 12. This mutation has been reported in several hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome cohorts (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Niessen RC et al. Gut, 2006 Dec;55:1781-8; Kamiza AB et al. PLoS ONE, 2015 Jun;10:e0130018). 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	RCV000629963	SCV000750919	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser612*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15849733, 16636019, 26053027). ClinVar contains an entry for this variant (Variation ID: 90799). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491040	SCV001354538	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 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 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.
GeneDx	RCV000202183	SCV002569839	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 17192056, 15849733, 19419416, 26053027, 16636019, 31830689)
Myriad Genetics, Inc.	RCV003452860	SCV004188072	pathogenic	Lynch syndrome 1	2023-08-03	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202183	SCV000257154	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357329	SCV001552771	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Ser612X variant was identified in 3 of 4004 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Mangold 2005, Nielsen 2006). The variant was also identified in dbSNP (ID: rs63750493) as “With Pathogenic allele”, Clinvitae and ClinVar database (classified as pathogenic by InSight and Mayo Clinic), COSMIC, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (as Pathogenic), and UMD (2x with a causal classification). The variant was not identified in the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the genome Aggregation Database (beta), “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Ser612X variant leads to a premature stop codon at position 612, which is predicted to lead to 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.