ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1477G>A (p.Asp493Asn) (rs148642064)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115658 SCV000149567 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1477G>A at the cDNA level, p.Asp493Asn (D493N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asp493Asn occurs at a position that is not conserved and is not located in a known functional domain. 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 Asp493Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000123080 SCV000166376 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 493 of the PMS2 protein (p.Asp493Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs148642064, ExAC 0.001%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127760). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Color RCV000583059 SCV000691018 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000115658 SCV001155031 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000583059 SCV001172067 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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