ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.481G>A (p.Ala161Thr) (rs193920817)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161027 SCV000211748 likely pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing This variant is denoted TP53 c.481G>A at the cDNA level, p.Ala161Thr (A161T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). Although TP53 Ala161Thr has not been reported as a germline variant to our knowledge, it has been observed as a frequent somatic variant in multiple tumor samples including gastric, large intestine, lung, hematopoietic, leiomyosarcoma and hepatocellular carcinoma (Miyajima 2001, Fricke 2003, Soussi 2005, Forbes 2014). In vitro assays show this variant to be temperature sensitive, exhibiting behavior similar to TP53 inactivating mutants (Shiraishi 2004, Pekova 2011). Although functional studies have found that this variant resulted in abnormal transcriptional activity as compared to wild type TP53 in a yeast assay (Kovvali 2001), other transactivation studies have demonstrated mixed results (Epstein 1998, Okada 2006). TP53 Ala161Thr was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Ala161Thr occurs at a position that is conserved through mammals and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider TP53 Ala161Thr to be a likely pathogenic variant.
Ambry Genetics RCV000214033 SCV000274909 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Invitae RCV000473543 SCV000545324 uncertain significance Li-Fraumeni syndrome 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 161 of the TP53 protein (p.Ala161Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 26681312, 18327210). ClinVar contains an entry for this variant (Variation ID: 161518). In vitro experimental studies performed in yeast have shown that his missense change results in a temperature sensitive cellular phenotype, comparable to TP53 inactivating mutants (PMID: 21232794), and in abnormal levels of TP53 transcriptional transactivation activity (PMID: 11222779). However, other transactivation studies performed in yeast and human cell lines have shown that this variant retains partial TP53 transcriptional transactivation function (PMID: 12826609, 16827139). 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.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761073 SCV000890988 uncertain significance Ganglioneuroblastoma 2016-10-31 criteria provided, single submitter clinical testing
Color RCV000214033 SCV000908792 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Science for Life laboratory, Karolinska Institutet RCV000149053 SCV000088695 unknown Malignant tumor of prostate no assertion criteria provided not provided Converted during submission to Uncertain significance.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785328 SCV000923896 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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