ClinVar Miner

Submissions for variant NM_000546.5(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 The p.A161T variant (also known as c.481G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 481. The alanine at codon 161 is replaced by threonine, an amino acid with similar properties. This alteration has been observed in a patient with personal and family history consistent with a diagnosis of Li-Fraumeni syndrome (Ambry internal data). It is located in the functionally critical DNA binding domain and has shown partially reduced or absent transactivation capacity in comparison to wild type in yeast-based functional studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Kovvali GK et al. Nucleic Acids Res., 2001 Mar;29:E28; Yamazaki Y et al. Oral Oncol., 2003 Feb;39:163-9; ). Additional studies in yeast demonstrated this alteration to be temperature sensitive with the mutant phenotype at 35<sup>â—¦</sup>C and the wild type phenotype at 25<sup>â—¦</sup>C (Pekova S et al. Leuk. Res. 2011 Jul;35:889-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761073 SCV000890988 likely pathogenic Li-Fraumeni syndrome 1 2020-08-18 criteria provided, single submitter clinical testing The TP53 c.481G>A (p.Ala161Thr) missense variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). It is located in a mutational hotspot defined as ≥ 10 somatic occurrences (PM1; cancerhotspots.org). The variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 55 (PP3). Additionally, transactivation assays show a partially functioning allele according to Kato et al., and there is evidence of a dominant negative effect and loss of function according to Giacomelli et al. (PS3_Moderate; PMID 12826609, 30224644). This variant has been reported in one family meeting classic Li-Fraumeni syndrome criteria (PMID: 29456621). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1: PM2_Supporting, PM1, PP3, PS3_Moderate.
Color Health, Inc 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 Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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