ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.764T>A (p.Ile255Asn) (rs876659675)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221023 SCV000276382 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Database of Curated Mutations (DoCM) RCV000433813 SCV000508702 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440110 SCV000508703 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422868 SCV000508704 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432689 SCV000508705 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441998 SCV000508706 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425285 SCV000508707 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432486 SCV000508708 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Invitae RCV000633370 SCV000754592 uncertain significance Li-Fraumeni syndrome 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 255 of the TP53 protein (p.Ile255Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a somatic variant in individuals affected with acute myeloid leukemia (PMID: 26781615, 26230955), but has not been reported as a germline variant in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 232289). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). A single amino acid deletion at this codon (p.Ile255del) has been reported as a de novo variant in an individual affected with breast cancer, and has been determined to be likely pathogenic (Invitae). Although the single amino acid deletion and the missense change may affect the function of the TP53 protein in different ways, this suggests that this isoleucine residue is critical for TP53 protein function. 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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