ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.363T>G (p.Tyr121Ter)

dbSNP: rs63750458
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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) RCV000076572 SCV000107604 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Color Diagnostics, LLC DBA Color Health RCV000580738 SCV000685083 pathogenic Hereditary cancer-predisposing syndrome 2022-12-13 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 2 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: 15713769) and familial colorectal cancer (PMID: 19698169, 22883484; Color internal data). 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 RCV001070054 SCV001235263 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-02-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr121*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with Lynch syndrome (PMID: 15713769, 22883484, 19698169). ClinVar contains an entry for this variant (Variation ID: 91070). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000580738 SCV002617825 pathogenic Hereditary cancer-predisposing syndrome 2020-12-11 criteria provided, single submitter clinical testing The p.Y121* pathogenic mutation (also known as c.363T>G), located in coding exon 2 of the MSH2 gene, results from a T to G substitution at nucleotide position 363. This changes the amino acid from a tyrosine to a stop codon within coding exon 2. This alteration was identified in multiple individuals diagnosed with colorectal cancer (Casey G et al. JAMA, 2005 Feb;293:799-809; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14) and in individuals diagnosed with urothelial cancer (Skeldon SC et al. Eur Urol, 2013 Feb;63:379-85). 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. RCV003452935 SCV004186847 pathogenic Lynch syndrome 1 2023-07-26 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.
Baylor Genetics RCV003452935 SCV004196942 pathogenic Lynch syndrome 1 2021-04-01 criteria provided, single submitter clinical testing

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