ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.28G>A (p.Val10Ile) (rs535274413)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000235217 SCV000884715 uncertain significance not provided 2017-06-20 criteria provided, single submitter clinical testing The TP53 c.28G>A;p.Val10Ile variant has been shown to function similarly to wild type in at least some functional studies (Kato 2003, Shiraishi 2004). The variant is listed in the ClinVar database (Variation ID: 127806) and the dbSNP variant database (rs535274413) with an allele frequency of 0.003258 percent (8/245572 alleles) in the Genome Aggregation Database. The amino acid at this position is weakly conserved across species and computational algorithms (Align GVGD, PolyPhen2, SIFT) predict this variant is tolerated, although the amino acid is located in the transactivation domain (Bode 2004). Considering available information, there is insufficient evidence to classify the variant with certainty. If this variant is later determined to be pathogenic, this individual would be at increased risk for development of hereditary cancers (OMIM#191170). References: Bode AM and Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004 Oct;4(10):793-805. Kato S et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Shiraishi K et al. Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library. J Biol Chem. 2004 Jan 2;279(1):348-55.
Ambry Genetics RCV000115717 SCV000184102 likely benign Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),in silico models in agreement (benign)
Color RCV000115717 SCV000911076 likely benign Hereditary cancer-predisposing syndrome 2015-04-25 criteria provided, single submitter clinical testing
Counsyl RCV000662410 SCV000784841 uncertain significance Li-Fraumeni syndrome 1 2017-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000235217 SCV000149626 uncertain significance not provided 2018-10-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.28G>A at the cDNA level, p.Val10Ile (V10I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant co-occurred with CDH1 c.521dupA in two individuals with breast cancer undergoing multigene panel testing (Tung 2015) and 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 Val10Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the transactivation domain (Bode 2004, Pessoa 2014). 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 Val10Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781916 SCV000920321 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: TP53 c.28G>A (p.Val10Ile) results in a conservative amino acid change located in the p53 transactivation domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245572 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.28G>A has been reported in the literature in individuals affected with breast cancer, in one case with a co-occurrence with a pathogenic variant (CDH1 c.521dupA, p.Asn174Lysfs*25), providing supporting evidence for a benign role (Tung_2016). This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with one submission of likely benign and two submissions of VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000203717 SCV000260029 uncertain significance Li-Fraumeni syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 10 of the TP53 protein (p.Val10Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs535274413, ExAC 0.03%). This variant has been reported in the literature in individuals affected with breast cancer who also carried a pathogenic variant in CDH1 (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 127806). 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.
Mendelics RCV000203717 SCV000839130 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing

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