ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.393C>A (p.Asn131Lys) (rs769270327)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492741 SCV000581099 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000492741 SCV000903736 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000236166 SCV000293984 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.393C>A at the cDNA level, p.Asn131Lys (N131K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported in a colorectal tumor, along with another TP53 missense variant, and a myeloid neoplasm (Cleven 2015, Jauhri 2017). This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Asn131Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). TP53 Asn131Lys is located within the DNA binding domain (Bode 2004). 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 Asn131Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000465360 SCV000545263 uncertain significance Li-Fraumeni syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 131 of the TP53 protein (p.Asn131Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs769270327, ExAC 0.002%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 246429). An experimental study in yeast has shown that this variant partially impairs 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.

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