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Gene Symbol MDM2
Synonyms ACTFS | hdm2 | HDMX | LSKB
Gene Description MDM2, MDM2 proto-oncogene, is an E3 ubiquitin protein ligase that mediates Tp53 degradation and therefore, regulates apoptosis and cell-cycle (PMID: 27993876). Amplification and/or overexpression of MDM2 has been identified in several cancer types (PMID: 23303139, PMID: 31440117) and amplification is common in liposarcoma (PMID: 30237864) and has been observed with Mdm2 overexpression in anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (PMID: 32195970).
NCBI Gene ID Chromosome Map Location Canonical Transcript Gene Role
4193 12 12q15 NM_001367990 Oncogene (PMID: 30606230)

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
A49E missense no effect - predicted MDM2 A49E (corresponding to A43E in the canonical isoform) lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). A49E demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.
act mut unknown gain of function MDM2 act mut indicates that this variant results in a gain of function in the Mdm2 protein. However, the specific amino acid change has not been identified.
amp none no effect MDM2 amp indicates an increased number of copies of the MDM2 gene. However, the mechanism causing the increase is unspecified.
C2A missense no effect - predicted MDM2 C2A lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). C2A demonstrates binding to Tp53 similar to wild-type Mdm2 in an in vitro assay (PMID: 9131587), and therefore, is predicted to have no effect on Mdm2 protein function.
C305F missense loss of function MDM2 C305F lies within the RanBP2-type zinc finger domain of the Mdm2 protein (UniProt.org). C305F retains Tp53 binding and transcriptional inhibition but confers a loss of function to Mdm2 as demonstrated by impaired nuclear export, failure to bind the ribosomal proteins L5 or L11, and failure to mediate Tp53 degradation in culture (PMID: 17116689).
C308W missense loss of function MDM2 C308W lies within the RanBP2-type zinc finger domain of the Mdm2 protein (UniProt.org). C308W confers a loss of function to Mdm2 as demonstrated by loss of binding to the ribosomal proteins L11, L5 or L23 in in vitro assays (PMID: 21903592).
C308Y missense loss of function - predicted MDM2 C308Y lies within the RanBP2-type zinc finger domain of the Mdm2 protein (UniProt.org). C308Y results in decreased Tp53 degradation (PMID: 17116689) and has been shown to confer MDM2 inhibitor resistance in cell culture (PMID: 23653682), and therefore, is predicted to lead to a loss of Mdm2 protein function. Y
C319R missense loss of function - predicted MDM2 C319R lies within the RanBP2-type zinc finger domain of the Mdm2 protein (UniProt.org). C319R results in decreased binding of Mdm2 to ribosomal protein L11 (PMID: 21903592), and therefore, is predicted to lead to a loss of Mdm2 protein function.
C447A missense no effect MDM2 C447A (corresponding to C441A in the canonical isoform) lies within the RING-type zinc finger domain of the Mdm2 protein (UniProt.org). C447A demonstrates self-ubiquitination, Tp53 degradation, and effects on cell cycle similar to wild-type Mdm2 in cultured cells (PMID: 10951578).
C447S missense loss of function - predicted MDM2 C447S (corresponding to C441S in the canonical isoform) lies within the RING-type zinc finger domain of the Mdm2 protein (UniProt.org). C447S results in loss of Mdm2 protein ubiquitination activity and ability to degrade Tp53 (PMID: 27308622), and therefore, is predicted to lead to a loss of Mdm2 protein function.
C464A missense loss of function MDM2 C464A lies within the RING-type zinc finger region of the Mdm2 protein (UniProt.org). C464A results in a loss of E3 ubiquitin ligase activity and Mdm2 self-ubiquitination (PMID: 30217928), failure to ubiquitinate and degrade Tp53 (PMID: 10980696, PMID: 17848574), Arc (PMID: 17142834), and Ar (PMID: 12145204), and inability to degrade Rb through proteasome-dependent mechanism in culture (PMID: 16337594).
C470Y missense loss of function - predicted MDM2 C470Y (corresponding to C464Y in the canonical isoform) lies within the RING-type zinc finger domain of the Mdm2 protein (UniProt.org). C470Y fails to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a loss of Mdm2 protein function.
C77A missense loss of function - predicted MDM2 C77A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). C77A results in loss of Tp53 binding in an in vitro assay (PMID: 9131587), and therefore, is predicted to lead to a loss of Mdm2 protein function.
C77Y missense loss of function - predicted MDM2 C77Y lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). C77Y results in loss of Tp53 binding in an in vitro assay (PMID: 9131587), and therefore, is predicted to lead to a loss of Mdm2 protein function.
D68A missense loss of function MDM2 D68A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). D68A confers a loss of function to Mdm2 as demonstrated by loss of TP53 binding in an in vitro assay and failure to inhibit Tp53 transcriptional activity in a cell-based assay (PMID: 9131587).
D86Y missense loss of function - predicted MDM2 D86Y (corresponding to D80Y in the canonical isoform) lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). D86Y confers a loss of function to the Mdm2 protein as indicated by failure to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a loss of Mdm2 protein function.
E69A missense loss of function - predicted MDM2 E69A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). E69A results in decreased binding to TP53 in an in vitro assay (PMID: 9131587), and therefore, is predicted to lead to a loss of Mdm2 protein function.
G58A missense loss of function MDM2 G58A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). G58A confers a loss of function to Mdm2 as demonstrated by loss of TP53 binding in an in vitro assay and failure to inhibit Tp53 transcriptional activity in a cell-based assay (PMID: 9131587).
G58D missense loss of function - predicted MDM2 G58D lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). G58D results in loss of Tp53 binding in an in vitro assay (PMID: 9131587), and therefore, is predicted to lead to a loss of Mdm2 protein function.
inact mut unknown loss of function MDM2 inact mut indicates that this variant results in a loss of function of the Mdm2 protein. However, the specific amino acid change has not been identified.
L205Q missense no effect - predicted MDM2 L205Q (corresponding to L199Q in the canonical isoform) lies within the MTBP-interacting region of the Mdm2 protein (UniProt.org). L205Q demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.
L82P missense unknown MDM2 L82P lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). L82P has been associated with MDM2 inhibitor resistance in cell culture (PMID: 23653682), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Jun 2022). Y
M459T missense unknown MDM2 M459T lies within the RING-type zinc finger domain of the Mdm2 protein (UniProt.org). M459T has not been characterized in the scientific literature and therefore, its effect on Mdm2 protein function is unknown (PubMed, Dec 2022).
M465I missense gain of function - predicted MDM2 M465I (corresponding to M459I in the canonical isoform) lies within the RING-type zinc finger domain of the Mdm2 protein (UniProt.org). M465I results in increased Tp53 degradation in culture (PMID: 27308622), and therefore, is predicted to lead to a gain of Mdm2 protein function.
M465L missense loss of function - predicted MDM2 M465L (corresponding to M459 in the canonical isoform) lies within the RING-type zinc finger domain of the Mdm2 protein (UniProt.org). M465L fails to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a loss of Mdm2 protein function.
M465V missense no effect - predicted MDM2 M465V (corresponding to M459V in the canonical isoform) lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). M465V demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.
M62A missense unknown MDM2 M62A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). M62A has been shown to confer MDM2 inhibitor resistance in cell culture (PMID: 23653682, PMID: 29121928, PMID: 25115702), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Jun 2022). Y
M62V missense unknown MDM2 M62V lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). M62V has been shown to confer MDM2 inhibitor resistance in cell culture (PMID: 23653682), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Jun 2022). Y
mutant unknown unknown MDM2 mutant indicates an unspecified mutation in the MDM2 gene.
negative unknown loss of function MDM2 negative indicates a lack of expression of the MDM2 mRNA and/or protein.
over exp none no effect MDM2 over exp indicates an over expression of the Mdm2 protein. However, the mechanism causing the over expression is unspecified.
P20L missense unknown MDM2 P20L lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). P20L has been shown to confer moderate MDM2 inhibitor resistance in cell culture (PMID: 23653682, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Jun 2022). Y
positive unknown unknown MDM2 positive indicates the presence of the MDM2 gene, mRNA, and/or protein.
Q24R missense unknown MDM2 Q24R lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). Q24R has been shown to confer MDM2 inhibitor resistance in culture (PMID: 23653682, PMID: 15953616, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Jun 2022). Y
R189C missense loss of function - predicted MDM2 R189C (corresponding to R183C in the canonical isoform) lies within the MTBP-interacting region of the Mdm2 protein (UniProt.org). R189C confers a loss of function to the Mdm2 protein as indicated by failure to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a loss of Mdm2 protein function.
R189H missense no effect - predicted MDM2 R189H (corresponding to R183H in the canonical isoform) lies within the MTBP-interacting region of the Mdm2 protein (UniProt.org). R189H demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.
R65* nonsense loss of function - predicted MDM2 R65* results in a premature truncation of the Mdm2 protein at amino acid 65 of 491 (UniProt.org). Due to the loss of most known functional domains (UniProt.org), R65* is predicted to lead to a loss of Mdm2 protein function.
R71Q missense no effect - predicted MDM2 R71Q (corresponding to R65Q in the canonical isoform) lies within the SWIB domain of the Mdm2 protein (UniProt.org). R71Q demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.
S17D missense gain of function MDM2 S17D lies within the lid region of the Mdm2 protein (PMID: 12552135). S17D stabilizes MDM2-TP53 binding and enhances Tp53 protein ubiquitination in an in vitro assay (PMID: 19568783, PMID: 20303977).
S394A missense loss of function MDM2 S394A (corresponding to S388A in the canonical isoform) lies within the region of the Mdm2 protein necessary for USP2 interaction (UniProt.org). S394A prevents ATM phosphorylation of Mdm2 Ser394, and subsequently reduces DNA damage-induced p53 activation (PMID: 22624716, PMID: 22624708).
S395D missense loss of function MDM2 S395D lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). S395D results in decreased Mdm2 protein stability (PMID: 17936559), impaired nuclear export and degradation of Tp53 (PMID: 11331603, PMID: 14654783), leads to activation of Tp53 and increased apoptosis in cell culture (PMID: 22264786).
S435R missense gain of function - predicted MDM2 S435R (corresponding to S429R in the canonical isoform) lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). S435R demonstrates increased ability to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a gain of Mdm2 protein function.
T16A missense unknown MDM2 T16A lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). T16A has been shown to confer moderate MDM2 inhibitor resistance in cell culture (PMID: 23653682), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Jun 2022). Y
T16I missense unknown MDM2 T16I lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). T16I has been identified in sequencing studies (PMID: 22138691), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Dec 2022).
V234L missense no effect - predicted MDM2 V234L (corresponding to V228L in the canonical isoform) lies within the ARF-binding region of the Mdm2 protein (UniProt.org). V234L demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.
V247A missense unknown MDM2 V247A lies within the acidic domain of the Mdm2 protein (PMID: 14707282). V247A has not been characterized in the scientific literature and therefore, its effect on Mdm2 protein function is unknown (PubMed, Dec 2022).
V457A missense loss of function - predicted MDM2 V457A (corresponding to V451A in the canonical isoform) lies within the RING-type zinc finger domain of the Mdm2 protein (UniProt.org). V457A results in failure to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a loss of Mdm2 protein function.
V75A missense loss of function MDM2 V75A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). V75A confers a loss of function to Mdm2 as demonstrated by loss of TP53 binding in an in vitro assay and failure to inhibit Tp53 transcriptional activity in a cell-based assay (PMID: 9131587).
V94M missense loss of function - predicted MDM2 V94M (corresponding to V88M in the canonical isoform) lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). V94M confers a loss of function to the Mdm2 protein as indicated by failure to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a loss of Mdm2 protein function.
W335G missense no effect - predicted MDM2 W335G (corresponding to W329G in the canonical isoform) lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). W335G demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.
W335L missense gain of function - predicted MDM2 W335L (corresponding to W329L in the canonical isoform) lies within a region of the Mdm2 protein necessary for interaction wtih USP2 (UniProt.org). W335L demonstrates increased ability to degrade Tp53 in culture (PMID: 27308622), and therefore, is predicted to lead to a gain of Mdm2 protein function.
wild-type none no effect Wild-type MDM2 indicates that no mutation has been detected within the MDM2 gene.
Y287C missense no effect - predicted MDM2 Y287C (corresponding to Y281C in the canonical isoform) lies within the MTBP-interacting region of the Mdm2 protein (UniProt.org). Y287C demonstrates ability to degrade Tp53 similar to wild-type Mdm2 in culture (PMID: 27308622), and therefore, is predicted to have no effect on Mdm2 protein function.