ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.399G>A (p.Met133Ile)

gnomAD frequency: 0.00001  dbSNP: rs1064795139
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484833 SCV000570644 uncertain significance not provided 2016-06-13 criteria provided, single submitter clinical testing This variant is denoted TP53 c.399G>A at the cDNA level, p.Met133Ile (M133I) 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 as a germline pathogenic or benign variant. TP53 Met133Ile is reported as having functional transactivation capacities in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. TP53 Met133Ile occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within 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 Met133Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000662907 SCV000785831 uncertain significance Li-Fraumeni syndrome 1 2017-12-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001052030 SCV001216219 uncertain significance Li-Fraumeni syndrome 2023-12-12 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 133 of the TP53 protein (p.Met133Ile). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 32191290). ClinVar contains an entry for this variant (Variation ID: 421437). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484833 SCV001469320 uncertain significance not provided 2019-12-17 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289639 SCV002582091 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000662907 SCV002582653 uncertain significance Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV002289639 SCV002625676 likely benign Hereditary cancer-predisposing syndrome 2022-07-18 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Myriad Genetics, Inc. RCV000662907 SCV004017865 uncertain significance Li-Fraumeni syndrome 1 2023-04-11 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV004568185 SCV005054352 uncertain significance Adrenocortical carcinoma, hereditary 2023-11-27 criteria provided, single submitter clinical testing

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