ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1804C>G (p.Leu602Val) (rs748797209)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205416 SCV000259674 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 602 of the MSH2 protein (p.Leu602Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs748797209, ExAC 0.001%). This variant has been observed in several individuals affected with uterine, colon, and renal cancer (Invitae). However, in one of these individuals a pathogenic allele was also identified in MSH2, which suggests that this c.1804C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 219668). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000221565 SCV000275993 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235312 SCV000293865 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1804C>G at the cDNA level, p.Leu602Val (L602V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Leu602Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Lever domain as well as the region of interaction with MSH6, MSH3, and EXO1 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Leu602Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000221565 SCV000684978 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing
Counsyl RCV000663070 SCV000786137 uncertain significance Lynch syndrome I 2018-03-07 criteria provided, single submitter clinical testing

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