ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.419A>G (p.Asn140Ser) (rs876661103)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223561 SCV000279537 uncertain significance not provided 2015-11-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.419A>G at the cDNA level, p.Asn140Ser (N140S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asn140Ser 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 Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. PMS2 Asn140Ser occurs at a position that is not conserved and is located within the ATPase domain (Fukui 2011). 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 Asn140Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000697241 SCV000825838 uncertain significance Hereditary nonpolyposis colon cancer 2018-01-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 140 of the PMS2 protein (p.Asn140Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. 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: 234590). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV001022026 SCV001183714 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing Insufficient evidence

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