ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1828A>G (p.Lys610Glu) (rs199700509)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168273 SCV000218945 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 610 of the PMS2 protein (p.Lys610Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs199700509, ExAC 0.004%). This variant has been reported in an individual affected with lung cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 188287). 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 glutamic 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. 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.
GeneDx RCV000486825 SCV000567198 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1828A>G at the cDNA level, p.Lys610Glu (K610E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has been reported in an individual with lung cancer (Lu 2015). 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). This variant 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 Lys610Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574365 SCV000663448 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000574365 SCV000902934 likely benign Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000486825 SCV001155028 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing

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