ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1547G>T (p.Ser516Ile) (rs373564353)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409878 SCV000489292 uncertain significance Lynch syndrome I 2016-09-14 criteria provided, single submitter clinical testing
Invitae RCV000524347 SCV000548195 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 516 of the MSH2 protein (p.Ser516Ile). The serine residue is weakly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs373564353, ExAC 0.001%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 90694). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 26333163). 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.
GeneDx RCV000485690 SCV000569296 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1547G>T at the cDNA level, p.Ser516Ile (S516I) at the protein level, and results in the change of a Serine to an Isoleucine (AGT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser516Ile was not observed in large population cohorts (Lek 2016). Since Serine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ser516Ile occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located within the Clamp domain and a region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ser516Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001012071 SCV001172474 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-09 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001012071 SCV001343691 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-22 criteria provided, single submitter clinical testing

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