rs387906651

Variant names:

• chr14-65093782-G-A
• rs387906651
• NM_002382.5:c.97C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-65093782-G-A
• chr14-65093782-G-C
• chr14-65093782-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001320415.2(MAX):​c.-178C>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX NM_001320415.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.75

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]

ENSG00000259118 (HGNC:58293):

LOC100506321 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.625
• PP5: Variant 14-65093782-G-A is Pathogenic according to our data. Variant chr14-65093782-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-65093782-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAX	NM_002382.5	c.97C>T	p.Arg33*	stop_gained	Exon 3 of 5	ENST00000358664.9	NP_002373.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAX	ENST00000358664.9	c.97C>T	p.Arg33*	stop_gained	Exon 3 of 5	1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:1

Sep 17, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). ClinVar contains an entry for this variant (Variation ID: 29788) classified as Pathogenic . For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 07, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R33* pathogenic mutation (also known as c.97C>T), located in coding exon 3 of the MAX gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from an arginine to a stop codon within coding exon 3. This alteration has been reported in numerous individuals diagnosed with early-onset pheochromocytoma and paraganglioma (Comino-Méndez I et al. Nat. Genet. 2011 Jun;43:663-7; Burnichon N et al. Clin. Cancer Res. 2012 May;18:2828-37). This mutation was also identified in a 25 year-old male with multiple bilateral pheochromocytomas and bilateral adrenal medullary hyperplasia with all demonstrating negative MAX immunostaining (Romanet P et al. Endocr. Pathol. 2016 Nov [epub ahead of print]). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). ClinVar contains an entry for this variant (Variation ID: 29788). For these reasons, this variant has been classified as Pathogenic. -

Pheochromocytoma, susceptibility to Other:1

Jun 19, 2011

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.87
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906651; hg19: chr14-65560500; COSMIC: COSV52415510; COSMIC: COSV52415510;