ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.214_215delinsTG (p.Pro72Cys) (rs730882014)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587915 SCV000211787 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing This variant is denoted TP53 c.214_215delCCinsTG at the cDNA level and p.Pro72Cys (P72C) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is TCCC[delCC][insTG]CGTG. This in frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of a Proline to a Cysteine (CCC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TP53 Pro72Cys was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Proline and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Pro72Cys occurs at a position that is not conserved and is located within the SH3 domain (Bode 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Pro72Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000161055 SCV000215338 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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 2018-12-03 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 1 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 RCV000161055 SCV000686727 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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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