ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.71A>C (p.His24Pro) (rs139233015)

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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 RCV000166828 SCV000217642 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000459353 SCV000552044 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-09 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 24 of the PMS2 protein (p.His24Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs139233015, ExAC 0.02%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 187134). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000166828 SCV000686230 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588792 SCV000697379 uncertain significance not provided 2016-06-16 criteria provided, single submitter clinical testing Variant summary: Variant summary: The c.71A>C (p.His24Pro) in PMS2 gene is a missense variant involves a highly conserved nucleotide and in silico tools predict deleterious outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.00002 (2/115316 chrs tested), which does not exceed the maximal expected allele frequency for a non-common pathogenic variant (0.0001). The variant has not, to our knowledge been reported in affected individuals via published reports. In addition, the variant of interest has been reported as VUS by a reputable database/clinical laboratory. Taken all together, the variant was classified as VUS, until more data becomes available.

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