ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.89A>G (p.Gln30Arg) (rs56203955)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164904 SCV000215592 likely benign Hereditary cancer-predisposing syndrome 2017-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Color RCV000164904 SCV000909683 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Counsyl RCV000410641 SCV000489607 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000482199 SCV000571957 uncertain significance not provided 2016-10-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.89A>G at the cDNA level, p.Gln30Arg (Q30R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln30Arg 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 Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln30Arg occurs at a position that is conserved across species 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 Gln30Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198290 SCV000254619 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 30 of the PMS2 protein (p.Gln30Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 185474). 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 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.

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