ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs772354334
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV001723804 SCV001949920 likely benign Li-Fraumeni syndrome 1 2020-10-27 reviewed by expert panel curation Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Ambry). In summary, TP53 c.480G>A (p.Met160Ile) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS2_Supporting, BS3_Supporting.
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.
Invitae RCV000542402 SCV000629827 uncertain significance Li-Fraumeni syndrome 2024-01-29 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). ClinVar contains an entry for this variant (Variation ID: 230758). Advanced modeling performed at Invitae incorporating data from internal and/or published 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 (Invitae). 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.

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