ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.251C>G (p.Thr84Ser) (rs864622274)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204858 SCV000259946 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 84 of the PMS2 protein (p.Thr84Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. 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: 219847). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000216278 SCV000273447 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410342 SCV000489298 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-09-13 criteria provided, single submitter clinical testing
GeneDx RCV000478536 SCV000565381 uncertain significance not specified 2017-05-16 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.251C>G at the cDNA level, p.Thr84Ser (T84S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Thr84Ser was not observed in approximately 4,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. PMS2 Thr84Ser occurs at a position that is not conserved and is located within the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Thr84Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000478536 SCV000918040 uncertain significance not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: PMS2 c.251C>G (p.Thr84Ser) results in a conservative amino acid change located in the Histidine kinase/HSP90-like ATPase of the encoded protein sequence, and is the first nucleotide of exon 4. Three of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 115026 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.251C>G has been reported in the literature in one individual affected with ALL (Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000216278 SCV001343153 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-24 criteria provided, single submitter clinical testing

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