Submissions for variant NM_000546.6(TP53):c.730G>A (p.Gly244Ser)

dbSNP: rs1057519989

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492366	SCV000581152	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	The p.G244S pathogenic mutation (also known as c.730G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 730. The glycine at codon 244 is replaced by serine, an amino acid with similar properties. This mutation has been reported as a germline alteration 3 times including in a patient with both osteosarcoma and rhabdomyosarcoma at 17 years of age in the IARC database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). In addition, this alteration was identified in a male patient diagnosed with four primary tumors between the ages of 38-56, and both of his daughters that were diagnosed with breast cancer at 29 and 30 years old (Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24). The p.G244S mutation segregated with disease in a Chinese family diagnosed with LFS (Hu H et al. Sci Rep. 2016 Jan;6:20221). Multiple yeast based functional studies have demonstrated a loss of transactivation capacity as well as dominant negative activity for this alteration (Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98; Brachmann RK et al. Proc. Natl. Acad. Sci. U.S.A. 1996 Apr; 93(9):4091-5; Monti P et al. Oncogene. 2002 Mar; 21(11):1641-8; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a 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). Based on internal structural analysis, this alteration is anticipated to result in a decrease in structural stability (Ambry internal data; Zhao K et al. J Biol Chem, 2001 Apr;276:12120-7). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633372	SCV000754594	pathogenic	Li-Fraumeni syndrome	2024-08-15	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 244 of the TP53 protein (p.Gly244Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary ciliary dyskinesia and follicular lymphoma and Li-Fraumeni syndrome and breast cancer (PMID: 18511570, 18628487, 24307375, 25925845, 26818906). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 376600). 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%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). This variant disrupts the p.Gly244 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16494995, 21343334, 22319594). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000492366	SCV002582468	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289524	SCV002583129	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476007	SCV004204279	pathogenic	Adrenocortical carcinoma, hereditary	2022-05-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289524	SCV004930357	pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26818906].
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257520	SCV001434346	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Laboratory for Genotyping Development, RIKEN	RCV003168616	SCV002758170	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332172	SCV004040611	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research