ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1150A>G (p.Met384Val)

gnomAD frequency: 0.00001  dbSNP: rs730882009
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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 RCV001527102 SCV001737947 likely benign Li-Fraumeni syndrome 1 2021-04-12 reviewed by expert panel curation This variant is absent from the gnomAD non-cancer v2.1.1 dataset (PM2_supporting). Transactivation assays show partial function according to Kato, et al (PMID: 12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli et al. (PMID: 30224644) (BS3_supporting). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.1150A>G; p.Met384Val 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: PM2_supporting; BS3_supporting, BP4, BS2_supporting. In this case, PM2_Supporting is not applied to final classification as there is sufficient evidence for codes to meet Likely Benign.
GeneDx RCV000213071 SCV000211770 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1150A>G at the cDNA level, p.Met384Val (M384V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TP53 Met384Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Met384Val occurs at a position that is moderately conserved across species and is located in the basic (repression of DNA-binding) region, which is also a region responsible for interaction with Coactivator-Associated Arginine Methyltransferase 1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Met384Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000161040 SCV000216174 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-24 criteria provided, single submitter clinical testing The p.M384V variant (also known as c.1150A>G), located in coding exon 10 of the TP53 gene, results from an A to G substitution at nucleotide position 1150. The methionine at codon 384 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in patients affected with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant showed partially reduced transactivation capacity in comparison to wild type in a yeast-based functional assay (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000195684 SCV000254626 uncertain significance Li-Fraumeni syndrome 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 384 of the TP53 protein (p.Met384Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 182939). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587685 SCV000697427 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The TP53 c.1150A>G (p.Met384Val) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121408 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health RCV000161040 SCV001347651 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-12 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 384 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant has a partial impact on function in yeast transactivation assays (IARC database; PMID: 12826609) and did not impact function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 33471991) or suspected Lynch Syndrome (PMID: 25980754). This variant has not been identified 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 RCV003407600 SCV004113455 uncertain significance TP53-related disorder 2022-11-30 criteria provided, single submitter clinical testing The TP53 c.1150A>G variant is predicted to result in the amino acid substitution p.Met384Val. The TP53 gene variant c.1150A>G is predicted to result in the amino acid substitution p.Met384Val. This variant was identified in an individual suspected of having Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant has not been observed in the gnomAD database, indicating this variant is rare. It has been reported in ClinVar multiple times as a variant of uncertain significance however by ClinGen expert panel is this variant assessed as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/182939/). Transactivation assays show partial function of this variant (Kato et al. 2002. PubMed ID: 12826609) and there is no evidence of a dominant negative effect or loss of function (Giacomelli et al. 2018. PubMed ID: 30224644). In summary, we interpret this variant as uncertain.
All of Us Research Program, National Institutes of Health RCV000195684 SCV004823712 uncertain significance Li-Fraumeni syndrome 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 384 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant has a partial impact on function in yeast transactivation assays (IARC database; PMID: 12826609) and did not impact function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 33471991) or suspected Lynch Syndrome (PMID: 25980754). This variant has not been identified 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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