ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1447G>T (p.Glu483Ter)

dbSNP: rs63749947
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076164 SCV000107181 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000076164 SCV000914301 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Invitae RCV001064013 SCV001228886 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 28874130, 17312306). ClinVar contains an entry for this variant (Variation ID: 90668). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu483*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
Clinical Genetics and Genomics, Karolinska University Hospital RCV001269568 SCV001449646 pathogenic not provided 2016-04-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV002390225 SCV002701552 pathogenic Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing The p.E483* pathogenic mutation (also known as c.1447G>T), located in coding exon 9 of the MSH2 gene, results from a G to T substitution at nucleotide position 1447. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in multiple HNPCC families of various ethnicities (Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13; Lagerstedt Robinson K et al. J. Natl. Cancer Inst. 2007 Feb;99:291-9; Valentin MD et al. Fam. Cancer 2011 Dec;10:641-7; Bonadona V et al. JAMA 2011 Jun;305:2304-10). 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 RCV002390225 SCV004356685 pathogenic Hereditary cancer-predisposing syndrome 2021-11-17 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 9 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: 12624141, 17312306, 21681552, 26437257, 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.

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