ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2475C>T (p.Ser825=) (rs776460258)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567886 SCV000670746 likely benign Hereditary cancer-predisposing syndrome 2016-04-15 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign;In silico models in agreement (benign)
Invitae RCV001052807 SCV001217034 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-30 criteria provided, single submitter clinical testing This sequence change affects codon 825 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 484247). 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.
Integrated Genetics/Laboratory Corporation of America RCV001192584 SCV001360815 uncertain significance not specified 2019-07-22 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2475C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a novel 5' prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.4e-05 in 145224 control chromosomes. 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.2475C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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