ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.730G>A (p.Gly244Ser) (rs1057519989)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492366 SCV000581152 pathogenic Hereditary cancer-predisposing syndrome 2018-08-20 criteria provided, single submitter clinical testing <span style="font-family:arial,sans-serif">The <span style="font-family:arial,sans-serif">p.G244S pathogenic mutation (also known as c.730G>A), located in coding exon 6 of the <span style="font-family:arial,sans-serif">TP53<span style="font-family:arial,sans-serif"> 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 somatic alteration 71 times, and 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. <span style="font-family:arial,sans-serif">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. <span style="font-family:arial,sans-serif">Carcinogenesis. 2007 Feb; 28(2):289-98; Brachmann RK et al. <span style="font-family:arial,sans-serif">Proc. Natl. <span style="font-family:arial,sans-serif">Acad<span style="font-family:arial,sans-serif">. Sci. U.S.A.<span style="font-family:arial,sans-serif"> 1996 Apr; 93(9):4091-5; Monti P et al. <span style="font-family:arial,sans-serif">Oncogene. 2002 Mar; 21(11):1641-8; Kato S et al. <span style="font-family:arial,sans-serif">Proc Natl <span style="font-family:arial,sans-serif">Acad<span style="font-family:arial,sans-serif"> Sci <span style="font-family:arial,sans-serif">USA. 2003 Jul 8;100(14):8424-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000633372 SCV000754594 pathogenic Li-Fraumeni syndrome 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 244 of the TP53 protein (p.Gly244Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Li-Fraumeni syndrome and breast cancer in families (PMID: 18511570, 26818906, 25925845), and has also been found in individuals affected with primary ciliary dyskinesia and follicular lymphoma (PMID: 18628487, 24307375). ClinVar contains an entry for this variant (Variation ID: 376600). Experimental studies have shown that this missense change disrupts the transcriptional transactivation function of the TP53 protein (PMID: 12826609). A different missense substitution at this codon (p.Gly244Asp) has been determined to be pathogenic (PMID: 16494995, 21343334, 22319594). This suggests that the glycine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Database of Curated Mutations (DoCM) RCV000421362 SCV000508160 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432031 SCV000508161 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441006 SCV000508162 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423748 SCV000508163 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434459 SCV000508164 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443654 SCV000508165 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426513 SCV000508166 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433704 SCV000508167 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442909 SCV000508168 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425382 SCV000508169 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436060 SCV000508170 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418805 SCV000508171 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426057 SCV000508172 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001257520 SCV001434346 pathogenic Rhabdomyosarcoma (disease) 2020-09-01 no assertion criteria provided provider interpretation

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