Submissions for variant NM_000546.6(TP53):c.480G>A (p.Met160Ile)

gnomAD frequency: 0.00001  dbSNP: rs772354334

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000542402	SCV001949920	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.480G>A variant in TP53 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 160 (p.Met160Ile). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). This variant has an allele frequency of 0.000003390 (4/1180050 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, PM2_Supporting. (Bayesian Points: -2; VCEP specifications version 2.1; 1/16/2025).
Ambry Genetics	RCV000218200	SCV000274415	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-02	criteria provided, single submitter	clinical testing	The p.M160I variant (also known as c.480G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 480. The methionine at codon 160 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in cohorts undergoing evaluation for inherited cancer predisposition (Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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 proficient at growth suppression and has no 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 amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000485502	SCV000569877	uncertain significance	not provided	2017-09-29	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.480G>A at the cDNA level, p.Met160Ile (M160I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or benign polymorphism; however, it has been reported as a somatic variant in multiple different tumor types (Waridel 1997, Lukas 2001, Janku 2014, Umemura 2014, Forbes 2015). This variant is reported as having partially functional transactivation capacity in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Met160Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. TP53 Met160Ile occurs at a position that is not conserved and is located in the DNA binding domain (Bode 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 Met160Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542402	SCV000629827	uncertain significance	Li-Fraumeni syndrome	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 160 of the TP53 protein (p.Met160Ile). This variant is present in population databases (rs772354334, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 29785153, 34284872). ClinVar contains an entry for this variant (Variation ID: 230758). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) did not meet the statistical confidence thresholds required to predict the impact of this variant on TP53 function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV000218200	SCV000686742	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 160 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown this variant to have neutral effect on TP53 protein function (PMID: 1282660, 29979965, 30224644). This variant has been reported in an individual affected with breast cancer (PMID 29785153). This variant has been identified in 3/251310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV000485502	SCV000806240	uncertain significance	not provided	2017-01-10	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000218200	SCV000822207	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000542402	SCV004823798	uncertain significance	Li-Fraumeni syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 160 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown this variant to have neutral effect on TP53 protein function (PMID: 1282660, 29979965, 30224644). This variant has been reported in an individual affected with breast cancer (PMID 29785153). This variant has been identified in 3/251310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.