ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1238_1239delinsGG (p.Lys413Arg) (rs587780041)

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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 RCV000115653 SCV000273383 likely benign Hereditary cancer-predisposing syndrome 2017-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000115653 SCV000910936 likely benign Hereditary cancer-predisposing syndrome 2016-03-28 criteria provided, single submitter clinical testing
GeneDx RCV000254680 SCV000149562 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1238_1239delAAinsGG at the cDNA level, p.Lys413Arg (K413R) at the protein level. The surrounding sequence is GAAAAAA[delAA][insGG]GACG. This in-frame deletion and insertion results in the missense change of a Lysine to an Arginine (AAA>AGG). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in lung adenocarcinoma (Lai 2016). PMS2 c.1238_1239delAAinsGG was not observed in large population cohorts (Lek 2016). This variant occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 c.1238_1239delAAinsGG is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000231250 SCV000285054 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-09 criteria provided, single submitter clinical testing This sequence change replaces replaces lysine with arginine at codon 413 of the PMS2 protein (p.Lys413Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine 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: 127756). 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 arginine 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.

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