Submissions for variant NM_000546.6(TP53):c.1000G>C (p.Gly334Arg)

gnomAD frequency: 0.00001  dbSNP: rs730882028

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000468644	SCV001142554	uncertain significance	Li-Fraumeni syndrome	2021-08-26	reviewed by expert panel	curation	This variant was found to co-segregate with disease in multiple affected family members, with 6 meioses observed across three families (PP1_Moderate; PMID: 32675277; Internal laboratory contributor, SCV000545272.7). This variant has been reported in 11 probands meeting Revised Chompret criteria (PS4; PMID: 32675277, 25584008, 23580068), internal laboratory contributors: SCV000216886.6, SCV000545272.7). This variant is absent in the gnomAD non-cancer cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in 9 60+ year old females without a cancer diagnosis (BS2; internal laboratory contributor, SCV000545272.7). Transactivation assays show retained function according to Kato, et al. A potential dominant negative effect as per Giacomelli should not be considered here, because this variant occurs in the oligomerization domain, which is required for dominant negative function. There is no evidence of a loss of function according to Giacomelli, et al., however Powers et al. shows a modest loss of function in colony suppression and transactivation in patient-derived cell lines (BS3; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.1000G>C; p.Gly334Arg is uncertain for Li-Fraumeni syndrome. This variant has been reported as a putative low penetrance founder variant in the Ashkenazi Jewish population (PMID:32675277). At this time, the TP53 VCEP cannot curate variants for low-penetrance designation. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BS2, PP1_Moderate, PS4, PM2_Supporting.
GeneDx	RCV000588363	SCV000211807	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	Observed in individuals with adrenocortical tumors or breast cancer who meet Chompret criteria, but also in several others whose personal and family histories are not suspicious for Li-Fraumeni syndrome (Ribeiro 2012, Rath 2013, Kanchi 2014, Couch 2015, Maxwell 2016, Powers 2020); Published functional studies demonstrate no impact on tetramer formation, colony formation, or cellular localization, normal or mildly impaired growth suppression, no dominant negative effect, and primarily functional transactivation; one study reported decreased thermal stability, but lacked positive controls (Kato 2003, Kawaguchi 2005, Wasserman 2015, Giacomelli 2018, Fischer 2018, Pinto 2020, Powers 2020); 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; This variant is associated with the following publications: (PMID: 25452441, 22040600, 24665023, 16007150, 23580068, 24448499, 25584008, 25503501, 27153395, 29955864, 32675277, 15510160, 30224644, 12826609, 32637605, 35043155, 32817165, 33300245, 34793697, 33449224)
Ambry Genetics	RCV000161073	SCV000216886	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	The p.G334R variant (also known as c.1000G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1000. The glycine at codon 334 is replaced by arginine, an amino acid with dissimilar properties. Residue G334 is the hinge residue between the α-helix and β-sheet in the tetramerization domain of the p53 protein (Clore et al. Nat Struct Biol. 1995 Apr;2(4):321-33) and has been shown to be sensitive to substitution through in vitro analysis and predictive modeling (Kawaguchi et al. Oncogene. 2005 Oct 20;24(46):6976-81; Higa et al. Genet Mol Biol. 2009 Jul;32(3):626-33). This alteration has been detected in multiple patients with childhood onset adrenal cortical carcinoma (ACC), primarily of Ashkenazi Jewish descent, (Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9; Ambry internal data), and an individual with triple positive breast cancer who met Chompret criteria for Li-Fraumeni Syndrome (Rath et al. Breast Cancer Res. Treat. 2013 May;139(1):193-8). Functional studies conducted in yeast and human cell lines have shown this variant is able to form tetramers, and has transactivation capacity and colony reduction activity similar to wild type (Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9; Giacomelli AO et al. Nat. Genet. 2018 10;50:1381-1387; Fischer NW et al. J. Natl. Cancer Inst. 2018 Dec;110:1418-1421; Powers J et al. Cancer Res. 2020 09;80:3732-3744). Wasserman et al. examined TP53 alterations in pediatric cases of ACC, and showed that patients with alterations that have near-WT transactivation capacity were less likely to have a strong family history of cancer. This alteration is absent from the non-cancer cohort of the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91), and has been observed primarily in individuals of Ashkenazi Jewish descent (Powers J et al. Cancer Res. 2020 09;80:3732-3744; Ambry internal data). This amino acid position is highly conserved in available vertebrate species and is predicted to be deleterious by in silico analysis. Based on current evidence, this alteration is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised.
Invitae	RCV000468644	SCV000545272	likely pathogenic	Li-Fraumeni syndrome	2024-01-04	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 334 of the TP53 protein (p.Gly334Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome, including adrenocortical tumors, breast cancer, and hematological malignancies. However, this variant has also been observed in unaffected individuals, which is suggestive of reduced penetrance (PMID: 23580068, 24448499, 25452441, 25503501, 25584008, 32675277; Invitae). ClinVar contains an entry for this variant (Variation ID: 182969). 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, 25584008, 29955864, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588363	SCV000697422	uncertain significance	not provided	2017-03-24	criteria provided, single submitter	clinical testing	Variant summary: The TP53 c.1000G>C (p.Gly334Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/117018 control chromosomes at a frequency of 0.0000085, which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). The variant has been reported in affected individuals in the literature with adrenocortical carcinoma, breast cancer and ovarian cancer, however strong evidence for causality was not included in these reports. Additionally, functional studies (transactivation induction and colony reduction studies) suggest the variant to have similar activity compared to WT (Wasserman_2015). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, until additional functional and clinical studies are available, this variant is classified as VUS.
Counsyl	RCV000663214	SCV000786400	uncertain significance	Li-Fraumeni syndrome 1	2018-04-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492643	SCV002775178	uncertain significance	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-05-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663214	SCV004017857	likely pathogenic	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25584008, 32675277]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25584008, 32675277].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588363	SCV004221342	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250586 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with adrenocortical tumors (PMID: 32675277 (2020)), and individuals with breast and/or ovarian cancer, many of whom meet Chompret criteria (PMIDs: 23580068 (2013), 24448499 (2014), 25452441 (2015), 25503501 (2015), 25584008 (2015), and 27153395 (2016)). Functional studies in yeast and human cell lines showed this variant can form tetramers, and transactivation capacity and colony reduction activity performed similar to wild type (PMID: 12826609 (2003), 25584008 (2015), 29955864 (2018), 30224644 (2018), 32675277 (2020)). The variant has also been reported to segregate with disease in multiple affected members from several families (PMID: 32675277 (2020)), as well as reported as a low penetrance founder variant in the Ashkenazi Jewish population (PMID:32675277 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.