ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.142G>A (p.Asp48Asn) (rs755665894)

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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 RCV000220384 SCV000277905 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000549401 SCV000625527 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 48 of the PMS2 protein (p.Asp48Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs755665894, ExAC 0.002%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 233518). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000780615 SCV000918034 uncertain significance not specified 2017-10-31 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.142G>A (p.Asp48Asn) variant involves the alteration of a conserved nucleotide that lies within the histidine kinase/HSP90-like ATPase domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/240414 control chromosomes at a frequency of 0.0000042, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). One clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985901 SCV001134579 uncertain significance not provided 2019-07-15 criteria provided, single submitter clinical testing

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