ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.508C>A (p.His170Asn) (rs876661152)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213923 SCV000279672 uncertain significance not provided 2015-12-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.508C>A at the cDNA level, p.His170Asn (H170N) at the protein level, and results in the change of a Histidine to an Asparagine (CAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 His170Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 His170Asn occurs at a position that is not conserved and is located in the ATPase domain (Fukui 2011, Guarne 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 His170Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000699509 SCV000828222 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-04-04 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 170 of the PMS2 protein (p.His170Asn). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234669). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV001023516 SCV001185414 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-27 criteria provided, single submitter clinical testing Insufficient evidence

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