ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.886C>T (p.Pro296Ser) (rs375553553)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475272 SCV000551963 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-27 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 296 of the PMS2 protein (p.Pro296Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs375553553, ExAC 0.02%). This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411034). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their 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 RCV000480563 SCV000565390 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.886C>T at the cDNA level, p.Pro296Ser (P296S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Pro296Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Pro296Ser occurs at a position that is conserved across species and is located within the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Pro296Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564830 SCV000674254 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-17 criteria provided, single submitter clinical testing Insufficient evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000564830 SCV000686251 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-23 criteria provided, single submitter clinical testing

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