ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2726A>T (p.Lys909Ile) (rs34319539)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198941 SCV000254416 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 909 of the MSH2 protein (p.Lys909Ile). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is present in population databases (rs34319539, ExAC 0.002%). This variant has been reported in the literature in individuals affected with colorectal cancer (PMID: 22581703, 15872200). ClinVar contains an entry for this variant (Variation ID: 216359) An experimental study has shown that this missense change does not affect MSH2 mismatch repair activity (PMID: 22581703). 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.
Ambry Genetics RCV000223226 SCV000278667 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000235290 SCV000293241 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2726A>T at the cDNA level, p.Lys909Ile (K909I) at the protein level, and results in the change of a Lysine to an Isoleucine (AAA>ATA). This variant was identified in an individual with colorectal cancer who also carried an MSH6 variant, and whose tumor displayed microsatellite instability (MSI-H), absence of MLH1 protein and presence of MSH2 and MSH6 proteins by immunohistochemistry (IHC); however in an in vitro assay, this variant did not display a significant decrease in repair efficiency compared to wild type, and when assessed in combination with the MSH6 variant, there was no compound contribution to mismatch repair deficiency (Hampel 2005, Kantelinen 2012). MSH2 Lys909Ile was not observed in large population cohorts (Lek 2016). This variant is located in the helix-turn-helix domain and the region of interaction with MSH3 and MSH6 (Guerrette 1998, Lutzen 2008, Kansikas 2011, Wielders 2017). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Lys909Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000412048 SCV000489431 uncertain significance Lynch syndrome I 2016-10-11 criteria provided, single submitter clinical testing
Color RCV000223226 SCV000690092 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-03 criteria provided, single submitter clinical testing

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