ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.433C>A (p.Gln145Lys) (rs786204133)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168105 SCV000218761 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 145 of the PMS2 protein (p.Gln145Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. 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: 188191). 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 tolerated, 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.
Ambry Genetics RCV000222089 SCV000275555 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000585952 SCV000565382 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.433C>A at the cDNA level, p.Gln145Lys (Q145K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln145Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln145Lys is located in the ATPase domain (Guarne 2001). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Gln145Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000222089 SCV000691075 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585952 SCV000697369 uncertain significance not provided 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.433C>A (p.Gln145Lys) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121284 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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