ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.554G>A (p.Ser185Asn) (rs150607408)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000233843 SCV001432166 likely benign Li-Fraumeni syndrome 2020-09-04 reviewed by expert panel curation Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, TP53 c.554G>A (p.Ser185Asn) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4.
Ambry Genetics RCV000129849 SCV000184666 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing The p.S185N variant (also known as c.554G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 554. The serine at codon 185 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported as a somatic mutation 2 times in various tumors and once as a germline mutation in an individual with osteosarcoma by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have functional transactivation capacity in yeast, (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100:8424-9) and proficient growth suppression in mammalian cells (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). This amino acid position is not well conserved in available vertebrate species and multiple species have asparagine as the reference amino acid. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000233843 SCV000285201 uncertain significance Li-Fraumeni syndrome 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 185 of the TP53 protein (p.Ser185Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs150607408, ExAC 0.01%). This variant has been observed in an individual affected with osteosarcoma (PMID: 25896519). ClinVar contains an entry for this variant (Variation ID: 141359). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (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.
Counsyl RCV000662659 SCV000785348 uncertain significance Li-Fraumeni syndrome 1 2017-07-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129849 SCV000906430 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing

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