Submissions for variant NM_000251.3(MSH2):c.1418C>G (p.Ser473Ter)

dbSNP: rs63751403

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076155	SCV000107171	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV002390224	SCV002697297	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-03	criteria provided, single submitter	clinical testing	The p.S473* pathogenic mutation (also known as c.1418C>G), located in coding exon 9 of the MSH2 gene, results from a C to G substitution at nucleotide position 1418. This changes the amino acid from a serine to a stop codon within coding exon 9. This variant has been identified in 1/32 Italian hereditary nonpolyposis ciolorectal cancer (HNPCC) families (Ponz de Leon M et al. Br. J. Cancer, 2004 Feb;90:882-7) . In another study, this alteration was detected in one patient diagnosed with colorectal cancer under the age of 40 years whose tumor showed microsatellite instability from a cohort 90 Italian colorectal cancer patients (Viel A et al. Community Genet, 1998;1:229-36). 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.
Myriad Genetics, Inc.	RCV003452832	SCV004188943	pathogenic	Lynch syndrome 1	2023-08-02	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000076155	SCV001553357	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Ser473X variant was identified in 3 of 338 proband chromosomes (frequency: 0.009) from Italian individuals or families with CRC, with/without family history or early onset in which affected patients carrying the variant had MSI-H tumours (Viel 1998, Ponz de Leon 2004, Capozzi 1999). The variant was also identified in dbSNP (ID: rs63751403) “With Pathogenic, Uncertain significance” alleles, ClinVar (classified as pathogenic, reviewed by expert panel; submitter InSIGHT), Clinvitae (1x), UMD-LSDB (1x as causal), Insight Colon Cancer Gene Variant Database (4x as causal), Mismatch Repair Genes Variant Database (4x), and Insight Hereditary Tumors Database (4X). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Ser473X variant leads to a premature stop codon at position 473, 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 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.