ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2266G>A (p.Asp756Asn) (rs762206330)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223544 SCV000279227 uncertain significance not provided 2015-11-05 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2266G>A at the cDNA level, p.Asp756Asn (D756N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp756Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asp756Asn occurs at a position that is not conserved across species, with Asparagine being the naturally occurring amino acid at this position in several species, and is located in the nuclease domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Asp756Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000465930 SCV000551996 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 756 of the PMS2 protein (p.Asp756Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234439). 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 asparagine 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. 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 RCV001014982 SCV001175761 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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