Submissions for variant NM_000546.6(TP53):c.322G>A (p.Gly108Ser)

dbSNP: rs587782461

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000458425	SCV001737939	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.322G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 108 (p.Gly108Ser). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; internal lab contributors). This variant received a total of 0.5 points across 1 proband (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000005932 (7/1180002 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0347; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting, BS3_Supporting, BP4. (Bayesian Points: -3; VCEP specifications version 2.1; 1/16/2025).
Ambry Genetics	RCV000131548	SCV000186548	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-13	criteria provided, single submitter	clinical testing	The p.G108S variant (also known as c.322G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 322. The glycine at codon 108 is replaced by serine, an amino acid with similar properties. The p.G108S alteration has been reported as a somatic alteration twice and has been reported once as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum. Mutat. 2007 Jun; 28(6):622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation capacity and no dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul; 100(14):8424-9; Sakuragi N et al. Int. J. Cancer. 2005 Sep; 116(4):514-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (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, with serine being the reference amino acid in lamprey. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.G108S remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000131548	SCV000292181	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 108 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be functional (PMID: 12826609 and IARC database, 29979965, 30224644). This variant has been observed in an individual affected with osteosarcoma (PMID: 25896519) an has not been reported in individuals affected with Li-Fraumeni syndrome in the literature. This variant has been identified in 3/251326 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	RCV000458425	SCV000545296	uncertain significance	Li-Fraumeni syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 108 of the TP53 protein (p.Gly108Ser). This variant is present in population databases (rs587782461, gnomAD 0.007%). This missense change has been observed in individual(s) with osteosarcoma (PMID: 25896519). ClinVar contains an entry for this variant (Variation ID: 142431). 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%. 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	RCV000679368	SCV000567174	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate partially functional transactivation, no dominant-negative effect, and no impact on growth suppression activity (PMID: 12826609, 15825182, 29979965, 30224644); Observed in an individual with osteosarcoma (PMID: 25896519); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27311873, 12826609, 27049831, 27566247, 14559903, 15825182, 11733960, 29979965, 28861920, 30840781, 15781620, 26875746, 30224644, 25896519, 15510160)
PreventionGenetics, part of Exact Sciences	RCV000679368	SCV000806237	uncertain significance	not provided	2018-01-05	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030738	SCV001193754	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Baylor Genetics	RCV003467176	SCV004206241	uncertain significance	Adrenocortical carcinoma, hereditary	2023-08-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000458425	SCV004823817	uncertain significance	Li-Fraumeni syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 108 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be functional (PMID: 12826609 and IARC database, 29979965, 30224644). This variant has been observed in an individual affected with osteosarcoma (PMID: 25896519) an has not been reported in individuals affected with Li-Fraumeni syndrome in the literature. This variant has been identified in 3/251326 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.