ClinVar Genomic variation as it relates to human health
NM_002382.5(MAX):c.295+1G>A
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002382.5(MAX):c.295+1G>A
Variation ID: 186993 Accession: VCV000186993.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q23.3 14: 65077912 (GRCh38) [ NCBI UCSC ] 14: 65544630 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 22, 2016 Feb 14, 2024 Sep 15, 2021 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- IVS4DS, G-A, +1
- Canonical SPDI
- NC_000014.9:65077911:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MAX | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
385 | 531 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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risk factor (1) |
no assertion criteria provided
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Jun 19, 2011 | RCV000022654.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2016 | RCV000166666.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2021 | RCV001850351.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000217471.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The c.295+1G>A pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MAX gene. This alteration has been … (more)
The c.295+1G>A pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MAX gene. This alteration has been identified in one individual with personal and family history of pheochromocytoma (PCC) in which the proband's PCC tumor demonstrated loss of heterozygosity as well as absent MAX staining via immunohistochemistry. In addition, RT-PCR analysis revealed that the c.295+1G>A allele was associated with complete skipping of exon 4 in tumor cDNA (Comino-Méndez I et al. Nat. Genet. 2011 Jul; 43(7):663-7). In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002240623.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminal domain of the MAX protein, which is essential for protein … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminal domain of the MAX protein, which is essential for protein localization to the nucleus and suppression of MYC transactivation activity (PMID: 1459463, 1730412, 7630640). While functional studies have not been performed to directly test the effect of this variant on MAX protein function, this suggests that disruption of this region of the protein is causative of disease. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 4 and introduces a new termination codon (PMID: 21685915). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 186993). Disruption of this splice site has been observed in individuals with pheochromocytoma and paraganglioma (PMID: 21685915, 22452945). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the MAX gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. (less)
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risk factor
(Jun 19, 2011)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000043943.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a 32-year-old man with bilateral malignant pheochromocytoma (171300), Comino-Mendez et al. (2011) identified a heterozygous G-to-A transition in intron 4 of the MAX gene … (more)
In a 32-year-old man with bilateral malignant pheochromocytoma (171300), Comino-Mendez et al. (2011) identified a heterozygous G-to-A transition in intron 4 of the MAX gene (295+1G-A), resulting in a splice site mutation and skipping of exon 4. Family history revealed a deceased brother and niece with unilateral pheochromocytoma. The mutation was not found in 750 control chromosomes. Studies of the tumor tissue showed a lack of full-length MAX protein and LOH of the MAX allele, which resulted from paternal UPD and loss of the maternal allele. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. | Burnichon N | Clinical cancer research : an official journal of the American Association for Cancer Research | 2012 | PMID: 22452945 |
Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. | Comino-Méndez I | Nature genetics | 2011 | PMID: 21685915 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Determination of sequences responsible for the differential regulation of Myc function by delta Max and Max. | Västrik I | Oncogene | 1995 | PMID: 7630640 |
Max: functional domains and interaction with c-Myc. | Kato GJ | Genes & development | 1992 | PMID: 1730412 |
Biphasic effect of Max on Myc cotransformation activity and dependence on amino- and carboxy-terminal Max functions. | Prendergast GC | Genes & development | 1992 | PMID: 1459463 |
Text-mined citations for rs786203385 ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.