ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.304G>A (p.Val102Ile) (rs193922373)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030251 SCV000107592 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics RCV000130254 SCV000185098 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient evidence
GeneDx RCV000657039 SCV000292988 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.304G>A at the cDNA level, p.Val102Ile (V102I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant was observed in at least one individual with a personal and family history that met Amsterdam I criteria; however, tumor testing from this individual revealed presence of MLH1 and MSH2 by immunohistochemistry and was microsatellite stable (Ward 2002). MSH2 Val102Ile was not observed at a significant allele frequnecy in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val102Ile is located within the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Val102Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000236541 SCV000539683 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: LB by expert panel
Invitae RCV000536977 SCV000625414 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 102 of the MSH2 protein (p.Val102Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs193922373, ExAC 0.006%). This variant has been reported in individuals with suspected Lynch syndrome (PMID: 12200596, 2695166). ClinVar contains an entry for this variant (Variation ID: 36575). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be tolerated (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000662359 SCV000784742 likely benign Lynch syndrome I 2017-01-16 criteria provided, single submitter clinical testing
Color RCV000130254 SCV000904003 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030251 SCV000052918 likely benign Lynch syndrome 2015-10-02 no assertion criteria provided clinical testing

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