ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.214_215delinsTG (p.Pro72Cys) (rs730882014)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000410841 SCV001737948 uncertain significance Li-Fraumeni syndrome 1 2021-04-12 reviewed by expert panel curation his variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, the clinical significance of TP53 c.214_215delinsTG (p.Pro72Cys) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS2_Supporting, PM2_Supporting.
GeneDx RCV000587915 SCV000211787 uncertain significance not provided 2020-09-16 criteria provided, single submitter clinical testing Located in the critical SH3 domain (Bode 2004) Not observed at a significant frequency in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant does not alter protein structure/function Published functional studies demonstrate retention of growth suppression activity and no dominant-negative effect (Giacomelli 2018)
Ambry Genetics RCV000161055 SCV000215338 likely benign Hereditary cancer-predisposing syndrome 2019-12-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410841 SCV000488534 uncertain significance Li-Fraumeni syndrome 1 2016-04-20 criteria provided, single submitter clinical testing
Invitae RCV000554325 SCV000629788 uncertain significance Li-Fraumeni syndrome 2020-09-08 criteria provided, single submitter clinical testing This sequence change replaces proline with cysteine at codon 72 of the TP53 protein (p.Pro72Cys). The proline residue is moderately conserved and there is a large physicochemical difference between proline and cysteine. This variant is reported as two separate single-nucleotide changes in the ExAC database (c.214C>T and c.215C>G), but the read data shows that the two variants are in cis, recapitulating the variant observed here (c.214_215delCCinsTG), in one individual. This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 182953). 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: Benign; Align-GVGD: Class 0). 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.
Color Health, Inc RCV000161055 SCV000686727 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587915 SCV000697436 uncertain significance not provided 2016-03-14 criteria provided, single submitter clinical testing Variant summary: The c.214_215delinsTG variant affects two nucleotides, resulting in amino acid change from Pro to Cys. One in-silico tool predicts benign outcome for this variant. This variant is not found in 120958 control chromosomes. In addition, multiple clinical laboratories/reputable database classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical 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 was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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