ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1723A>G (p.Asn575Asp) (rs142506484)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212863 SCV000149573 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1723A>G at the cDNA level, p.Asn575Asp (N575D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). PMS2 Asn575Asp has been identified in at least one individual with colon cancer, as well as in individuals undergoing multigene cancer panel testing due to a history of breast cancer or a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015, Pearlman 2016, Tung 2016). 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 (Lek 2016). PMS2 Asn575Asp is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether PMS2 Asn575Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115664 SCV000186208 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000195776 SCV000254606 uncertain significance Hereditary nonpolyposis colon cancer 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 575 of the PMS2 protein (p.Asn575Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs142506484, ExAC 0.005%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419) and an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127766). 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 aspartic acid 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.
Color RCV000115664 SCV000903240 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing

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