ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2175A>G (p.Ala725=) (rs769116749)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587820 SCV000697336 uncertain significance not provided 2017-03-13 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2175A>G (p.Ala725Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict the strenghtening of a canonical 5' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/73670 control chromosomes at a frequency of 0.0000136, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000803808 SCV000943694 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-29 criteria provided, single submitter clinical testing This sequence change affects codon 725 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 (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 496037). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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 RCV001014679 SCV001175416 likely benign Hereditary cancer-predisposing syndrome 2019-08-26 criteria provided, single submitter clinical testing

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