ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1555T>C (p.Tyr519His) (rs370236216)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199090 SCV000254599 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 519 of the PMS2 protein (p.Tyr519His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs370236216, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 216451). 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 histidine 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.
Ambry Genetics RCV000221963 SCV000273557 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000486619 SCV000565409 uncertain significance not provided 2018-07-27 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1555T>C at the cDNA level, p.Tyr519His (Y519H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, 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 evidence, it is unclear whether PMS2 Tyr519His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000221963 SCV000903477 likely benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780620 SCV000918042 uncertain significance not specified 2019-08-13 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1555T>C (p.Tyr519His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251302 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1555T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000987826 SCV001137293 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing

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