Submissions for variant NM_000251.3(MSH2):c.2575G>T (p.Glu859Ter)

dbSNP: rs63749830

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076506	SCV000107535	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV000794539	SCV000933953	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu859*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91004). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15849733, 20388775). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV001015992	SCV001176894	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	The p.E859* pathogenic mutation (also known as c.2575G>T), located in coding exon 15 of the MSH2 gene, results from a G to T substitution at nucleotide position 2575. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. This alteration was reported in a study of 1721 unrelated patients who met Bethesda criteria (Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702). A 42 year old patient with proximal colorectal cancer and loss of MSH2 expression on IHC was found to have this variant (Nagasaka T et al. Cancer Res. 2010 Apr;70:3098-108). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV001015992	SCV001355752	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 15 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.
Myriad Genetics, Inc.	RCV003452920	SCV004186843	pathogenic	Lynch syndrome 1	2023-08-09	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	RCV000076506	SCV000592552	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The p.Glu859X variant was identified in the literature in an individual with suspected Lynch syndrome (Mangold 2005). The variant was also identified in dbSNP (ID: rs63749830) “With pathogenic allele”, HGMD, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, and the ClinVar database (classified as pathogenic by InSiGHT). The p.Glu859X variant leads to a premature stop codon at position 859, 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.