ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.37C>T (p.Pro13Ser)

gnomAD frequency: 0.00001  dbSNP: rs1060501208
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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 RCV001724014 SCV001949913 uncertain significance Li-Fraumeni syndrome 1 2022-06-27 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). This variant has been reported in 2 probands meeting Revised Chompret criteria (PS4_Supporting; internal laboratory contributor). The TP53 VCEP allows classification of a variant as Likely Benign with two supporting benign evidence codes if there is only a single supporting pathogenic code. However, the group did not feel a classification of Likely Benign was appropriate for this variant at this time given that the BayesDel score is just below the VCEP threshold and considering the phenotypes reported in the families meeting Chompret criteria. In summary, the clinical significance of TP53 c.37C>T (p.Pro13Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, PS4_Supporting.
Invitae RCV000468196 SCV000545355 uncertain significance Li-Fraumeni syndrome 2023-03-07 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 406604). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 13 of the TP53 protein (p.Pro13Ser).
GeneDx RCV000478642 SCV000567854 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing This variant is denoted TP53 c.37C>T at the cDNA level, p.Pro13Ser (P13S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has been observed as a somatic variant in a cutaneous squamous cell carcinoma metastasis specimen (Li 2015). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Pro13Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Pro13Ser is located in the transactivation domain and in a nuclear export signal (Pessoa 2014, Bode 2004, Zhang 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether TP53 Pro13Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574176 SCV000667186 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-11 criteria provided, single submitter clinical testing The p.P13S variant (also known as c.37C>T), located in coding exon 1 of the TP53 gene, results from a C to T substitution at nucleotide position 37. The proline at codon 13 is replaced by serine, an amino acid with similar properties. This variant 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 (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000574176 SCV001347276 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing

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