ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.355G>T (p.Asp119Tyr) (rs587781913)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130256 SCV000185100 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-09 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000221783 SCV000279969 uncertain significance not provided 2016-03-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.355G>T at the cDNA level, p.Asp119Tyr (D119Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp119Tyr 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 Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Asp119Tyr occurs at a position that is conserved in mammals and is located within the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Asp119Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411252 SCV000489373 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-09-27 criteria provided, single submitter clinical testing
Invitae RCV000532710 SCV000625647 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 119 of the PMS2 protein (p.Asp119Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 141655). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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