Submissions for variant NM_000546.6(TP53):c.685T>C (p.Cys229Arg)

gnomAD frequency: 0.00001  dbSNP: rs1064794312

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482930	SCV000568760	uncertain significance	not provided	2024-11-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with adrenocortical carcinoma or breast cancer, none of whom have a family history consistent with Li-Fraumeni syndrome (PMID: 25584008, 28369373, 25925845); Published functional studies demonstrate no loss of growth suppression activity, partially functional transactivation per IARC, and intact or reduced transactivation of typical p53 targets per other studies (PMID: 12826609, 25584008, 29979965, 30224644); This variant is associated with the following publications: (PMID: 29979965, 25584008, 12826609, 25925845, 30840781, 28472496, 28222664, 30352134, 30224644, 28369373, 34298626, Nayak2023, 37593116, 37029683, 15510160, 34273903)
Ambry Genetics	RCV000492777	SCV000581119	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-05	criteria provided, single submitter	clinical testing	The p.C229R variant (also known as c.685T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 685. The cysteine at codon 229 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple breast cancer patients (Arcand SL et al. BMC Med. Genet., 2015 Apr;16:24; Zerdoumi Y et al. Hum Mol Genet, 2017 07;26:2591-2602). It has also been reported in three children with adrenocortical carcinoma, though one of the two patients also harbored a known TP53 mutation (R213*) (Wasserman JD et al. J. Clin. Oncol., 2015 Feb;33:602-9). Wasserman et al. also investigated the functional activity of ths alteration using a TP53- responsive luciferase reporter which showed increased transactivation capacity compared to wildtype (141%). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633388	SCV000754610	likely pathogenic	Li-Fraumeni syndrome	2024-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 229 of the TP53 protein (p.Cys229Arg). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 25584008, 25925845; internal data). ClinVar contains an entry for this variant (Variation ID: 420137). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 28369373, 29979965, 30224644). 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.
GenomeConnect, ClinGen	RCV000482930	SCV002074998	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-21-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.