Submissions for variant NM_000546.6(TP53):c.1078G>A (p.Gly360Arg)

gnomAD frequency: 0.00001  dbSNP: rs786203298

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166545	SCV000217347	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	The p.G360R variant (also known as c.1078G>A), located in coding exon 9 of the TP53 gene, results from a G to A substitution at nucleotide position 1078. The glycine at codon 360 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant 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 indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000166545	SCV001359323	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 360 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 33471991; DOI:10.5505/tjo.2020.2107). This variant has been identified in 2/281870 chromosomes 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241003	SCV001413992	uncertain significance	Li-Fraumeni syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 360 of the TP53 protein (p.Gly360Arg). This variant is present in population databases (rs786203298, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 186887). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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.
GeneDx	RCV001567714	SCV001791453	likely benign	not provided	2020-01-17	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 that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30224644, 14559903)
PreventionGenetics, part of Exact Sciences	RCV003416041	SCV004115787	uncertain significance	TP53-related disorder	2022-11-08	criteria provided, single submitter	clinical testing	The TP53 c.1078G>A variant is predicted to result in the amino acid substitution p.Gly360Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7573949-C-T). In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/186887/?new_evidence=false). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987388	SCV004803781	uncertain significance	not specified	2024-01-26	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.1078G>A (p.Gly360Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1078G>A in individuals affected with Li-Fraumeni Syndrome has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30224644, 12826609). ClinVar contains an entry for this variant (Variation ID: 186887). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV001241003	SCV004823720	uncertain significance	Li-Fraumeni syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 360 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 33471991; DOI:10.5505/tjo.2020.2107). This variant has been identified in 2/281870 chromosomes 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.