Submissions for variant NM_000546.6(TP53):c.676G>A (p.Gly226Ser)

dbSNP: rs1597365543

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802667	SCV000942508	uncertain significance	Li-Fraumeni syndrome	2023-12-31	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 226 of the TP53 protein (p.Gly226Ser). This variant is not present in population databases (gnomAD no frequency). 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: 648028). 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). 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.
Color Diagnostics, LLC DBA Color Health	RCV001524380	SCV001734204	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 226 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). Functional studies have shown the mutant protein to be functional in yeast transactivation assays (IARC database and PMID: 12826609) and in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in an individuals affected with colorectal cancer (PMID: 30267214). 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.
GeneDx	RCV002267028	SCV002549198	uncertain significance	not provided	2023-04-10	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; Published functional studies demonstrate no damaging effect: functional transactivation and no impact on growth suppression (Kato et al., 2003; Giacomelli et al., 2018; Kotler et al., 2018); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies assessing splicing impact, the actual effect of this sequence change is unknown.; Observed in an individual with colorectal cancer (Rosenthal et al., 2018); This variant is associated with the following publications: (PMID: 19509155, 22678923, 27146902, 29085664, 30224644, 29979965, 15510160, 30267214, 12826609, 22768918, 23117049)
Genome-Nilou Lab	RCV001524380	SCV002582023	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290444	SCV002582190	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001524380	SCV002662405	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-06	criteria provided, single submitter	clinical testing	The p.G226S variant (also known as c.676G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 676. The glycine at codon 226 is replaced by serine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have 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 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). In one study, this variant was detected in 1/165 colorectal cancer and/or polyposis patients and was identified in 0/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV000802667	SCV004823770	uncertain significance	Li-Fraumeni syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 226 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). Functional studies have shown the mutant protein to be functional in yeast transactivation assays (IARC database and PMID: 12826609) and in human cell growth assays (PMID: 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer 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.
Baylor Genetics	RCV004569592	SCV005054336	uncertain significance	Adrenocortical carcinoma, hereditary	2024-02-12	criteria provided, single submitter	clinical testing