Submissions for variant NM_000546.6(TP53):c.655C>T (p.Pro219Ser)

dbSNP: rs879253894

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705300	SCV000292697	uncertain significance	not provided	2019-12-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7966399, 25343854, 11004672, 11948487, 20128691, 21343334, 11358831, 14559903, 23117049, 10843195, 20575032, 23334666, 25584008, 24797764, 25925845, 17606709, 9445137, 15643509, 29979965, 31016814, 30840781, 30352134)
Ambry Genetics	RCV000492115	SCV000581085	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-18	criteria provided, single submitter	clinical testing	The p.P219S variant (also known as c.655C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 655. The proline at codon 219 is replaced by serine, an amino acid with similar properties. The p.P219S variant has been reported in multiple individuals diagnosed with childhood adrenocortical cancers (Wagner et al. J. Natl. Cancer Inst. 1994 Nov16;86(22):1707-10; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33:602-9; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24). This variant was also reported in a child with neuroblastoma (Pugh TJ et al. Nat. Genet. 2013;45(3):279-84; Seidinger AL et al. PLoS One. 2015 Oct;10:e0140356). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Other functional studies have shown that the mean residual luciferase activity for p.P219S was 34% compared to wild type, and the mean transactivation activity exceeded 90% of the wild-type allele alone. Authors concluded that the p.P219S is a partially deficient allele, and that partially deficient alleles were associated with a milder family history, a lower number of tumors, and a delayed disease onset than the severe deficiency alleles (Monti et al. Clin. Cancer Res. 2007 July;13(13):3789-3795; Monti et al. Mol. Cancer Res. 2011 Mar;9:271-279). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl	RCV000576805	SCV000677775	likely pathogenic	Li-Fraumeni syndrome 1	2016-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001065230	SCV001230180	likely pathogenic	Li-Fraumeni syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 219 of the TP53 protein (p.Pro219Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with adrenocortical carcinoma and breast cancer and neuroblastoma (PMID: 7966399, 25584008, 25925845, 26452166). ClinVar contains an entry for this variant (Variation ID: 245673). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 15221755, 20128691, 21343334, 25584008). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000576805	SCV004017877	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.