ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.539A>C (p.Glu180Ala)

dbSNP: rs1064793401
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484458 SCV000566024 uncertain significance not provided 2015-03-24 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.539A>C at the cDNA level, p.Glu180Ala (E180A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu180Ala 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 Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Glu180Ala occurs at a position that is conserved across species and is located in the ATPase domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Glu180Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001851145 SCV002221101 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-10-16 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with alanine at codon 180 of the PMS2 protein (p.Glu180Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. ClinVar contains an entry for this variant (Variation ID: 418740). 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. 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.
Ambry Genetics RCV002350053 SCV002650447 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-30 criteria provided, single submitter clinical testing The p.E180A variant (also known as c.539A>C), located in coding exon 6 of the PMS2 gene, results from an A to C substitution at nucleotide position 539. The glutamic acid at codon 180 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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