14-65077912-C-T

Position:

• chr14-65077912-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002382.5(MAX):​c.295+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX NM_002382.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.86

Genes affected

MAX (HGNC:6913): (MYC associated factor X) The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors. It is able to form homodimers and heterodimers with other family members, which include Mad, Mxi1 and Myc. Myc is an oncoprotein implicated in cell proliferation, differentiation and apoptosis. The homodimers and heterodimers compete for a common DNA target site (the E box) and rearrangement among these dimer forms provides a complex system of transcriptional regulation. Mutations of this gene have been reported to be associated with hereditary pheochromocytoma. A pseudogene of this gene is located on the long arm of chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

MAX (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.2, offset of 49, new splice context is: cagGTcagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-65077912-C-T is Pathogenic according to our data. Variant chr14-65077912-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 186993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-65077912-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-65077912-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAX	NM_002382.5	c.295+1G>A		splice_donor_variant, intron_variant		ENST00000358664.9	NP_002373.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAX	ENST00000358664.9	c.295+1G>A		splice_donor_variant, intron_variant		1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2016

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). -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2021

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. -

Pheochromocytoma, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 19, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.35	D
ClinPred		0.86	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.52		Position offset: -48
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786203385; hg19: chr14-65544630; COSMIC: COSV52419813; COSMIC: COSV52419813;