Submissions for variant NM_000546.6(TP53):c.322G>C (p.Gly108Arg)

dbSNP: rs587782461

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000527049	SCV000629803	uncertain significance	Li-Fraumeni syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 108 of the TP53 protein (p.Gly108Arg). This variant has not been reported in the literature in individuals affected with TP53-related conditions. 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) did not meet the statistical confidence thresholds required to predict the impact of this variant on TP53 function. ClinVar contains an entry for this variant (Variation ID: 458535).
Color Diagnostics, LLC DBA Color Health	RCV000777270	SCV000912972	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginie at codon 801 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have reported partial function in a yeast based transactivation assay (PMID: 12826609), functional in a human cell growth suppression assay (PMID: 30224644), and inconclusive in a human cell proliferation assay (PMID: 29979965). This variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000777270	SCV001180667	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	The p.G108R variant (also known as c.322G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 322. The glycine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (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 well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000527049	SCV001429672	uncertain significance	Li-Fraumeni syndrome	2019-10-11	criteria provided, single submitter	clinical testing	Data included in classification: UK family 1: proband with 3 primaries (breast cancer at 30 and 35, glioblastoma at 33). (PS4_sup) Variant absent from gnomAD controls (PM2_sup). Data not included in classification: Conflicting in silico class 0 on AlignGVGD and BayesDEL score 0.22 Functional studies: Kato et al, 2003 (PMID 12826609) Partially functional (between 20-75% activity) Giacomelli et al 2018 (PMID 30224644) - LOF only (unclassified) Other changes at codon suggested pathogenic (Gly108Asp), but only one reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886078/pdf/ddx106.pdf Parental samples not yet obtained, but have been requested to confirm if de novo or inherited.
Genome-Nilou Lab	RCV000777270	SCV002582118	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289728	SCV002582680	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003446143	SCV004171912	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459201	SCV004206258	uncertain significance	Adrenocortical carcinoma, hereditary	2023-07-10	criteria provided, single submitter	clinical testing