ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1163A>C (p.Glu388Ala) (rs587781736)

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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 RCV000226900 SCV001429626 likely benign Li-Fraumeni syndrome 2020-08-11 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 observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.1163A>C (p.Glu388Ala) 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, BS2_Supporting.
Ambry Genetics RCV000129934 SCV000184752 likely benign Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000226900 SCV000285173 uncertain significance Li-Fraumeni syndrome 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 388 of the TP53 protein (p.Glu388Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (rs587781736, ExAC no frequency). This variant has been reported in a family affected with breast cancer. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 26534844). ClinVar contains an entry for this variant (Variation ID: 141425). Experimental studies have shown that this variant does not affect TP53 transcriptional transactivation activity in yeast-based assays (PMID: 12826609), but disrupts SUMO-1 conjugation, a process which normally links TP53 to cellular protein targets (PMID: 11124955, 21900752). This impairs TP53 function resulting in increased Mic-1 induction, increased repression of Cdk1 and cyclinA2, and increased expression of p21 compared to wild-type TP53 (PMID: 21900752). The clinical significance of these data is uncertain. 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.
GeneDx RCV000236435 SCV000293950 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1163A>C at the cDNA level, p.Glu388Ala (E388A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). In one family, this variant was observed in two individuals with a personal history of breast cancer, in two unaffected individuals, and was absent in one individual with a personal history of breast cancer (Li 2016). Transactivation assays performed by Stindt et al. (2011) showed TP53 Glu288Ala as having varying levels of functional transactivation. Whereas, 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). In addition, nuclear localization is similar to wild-type p53 (Sindt 2011). TP53 Glu388Ala was not observed in large population cohorts (Lek 2016). Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Glu388Ala is located in the SUMO-1 modification motif within the C-terminal regulatory domain (Rodriguez 2001, Bode 2004, Stindt 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Glu388Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000129934 SCV000691579 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing

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