Submissions for variant NM_000546.6(TP53):c.482C>A (p.Ala161Asp)

dbSNP: rs1064795691

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481512	SCV000571725	likely pathogenic	not provided	2024-03-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16541312, 26895810, 11715068, 29979965, 10519380, 11590071, 16322298, 14559903, 26271412, 21071467, 12826609, 24836762, 26514544, 17121883, 30224644, 22768918, 15510160, 23117049)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552464	SCV000629828	uncertain significance	Li-Fraumeni syndrome	2017-03-22	criteria provided, single submitter	clinical testing	In summary, this variant is a rare missense change with that disrupts protein function in yeast and is absent from the population, but has also not been reported in the germline of any affected individual. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An experimental study has shown that this missense change disrupts TP53 transactivational activity in yeast (PMID: 12826609). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature as a germline variant in individuals with a TP53-related disease. This sequence change replaces alanine with aspartic acid at codon 161 of the TP53 protein (p.Ala161Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid.
Myriad Genetics, Inc.	RCV004023170	SCV004932945	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Ambry Genetics	RCV004686588	SCV005177928	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	The p.A161D variant (also known as c.482C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 482. The alanine at codon 161 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in blood specimens from breast and ovarian cancer patients (Dorling et al. N Engl J Med. 2021 02;384:428-439; Weber-Lassalle K et al. Hum Mutat, 2018 12;39:2040-2046), as well as breast and ovarian tumors (Hagio K et al. Sci Rep, 2021 04;11:8109; Sanders BE et al. Technol Cancer Res Treat;20:15330338211027917). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Another alteration at the same codon, p.A161T (c.481G>A), has been observed in multiple families with clinical histories consistent with a diagnosis of Li-Fraumeni syndrome (LFS) (Freitas AC et al. Ecancermedicalscience. 2018 Jan;12:804; Ambry internal data). In addition, the p.A161D alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.