Submissions for variant NM_000251.3(MSH2):c.2228C>G (p.Ser743Ter)

dbSNP: rs63751155

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076435	SCV000107464	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000491630	SCV000580398	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	The p.S743* pathogenic mutation (also known as c.2228C>G), located in coding exon 14 of the MSH2 gene, results from a C to G substitution at nucleotide position 2228. This changes the amino acid from a serine to a stop codon within coding exon 14. This mutation has been identified in an individual diagnosed with a colon carcinoma and a sebaceous carcinoma in their early 60's (Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72). 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.
Color Diagnostics, LLC DBA Color Health	RCV000491630	SCV000685026	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 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: 15235030, 15786548, 19324997, 27064304). 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.
Invitae	RCV000630114	SCV000751070	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser743*) 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 Muir-Torre syndrome (PMID: 15235030). ClinVar contains an entry for this variant (Variation ID: 90933). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000851293	SCV000993565	pathogenic	Lynch syndrome 1	2018-09-11	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV000851293	SCV004100517	pathogenic	Lynch syndrome 1		criteria provided, single submitter	clinical testing	The stop gained p.S743* in MSH2 (NM_000251.3) has been reported previously in an affected patient (Mangold E et al).This variant has been submitted to ClinVar as Pathogenic. The p.S743* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation.Loss of function variants have been reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000851293	SCV004187910	pathogenic	Lynch syndrome 1	2023-08-08	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	RCV001353876	SCV000592546	pathogenic	not provided		no assertion criteria provided	clinical testing