rs387906651

Positions:

• chr14-65093782-G-A
• chr14-65093782-G-C
• chr14-65093782-G-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.97C>T​(p.Arg33Ter) variant causes a stop gained 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_002382.5 stop_gained
• 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]

LOC100506321 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• 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/exons	MANE	UniProt
MAX	NM_002382.5	c.97C>T	p.Arg33Ter	stop_gained	3/5	ENST00000358664.9
LOC100506321	NR_045122.1	n.366G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAX	ENST00000358664.9	c.97C>T	p.Arg33Ter	stop_gained	3/5	1	NM_002382.5	P4

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

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Sep 17, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2017

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 mutation has been reported in numerous patients 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 pheochromoctyomas 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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29788). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). This variant is not present in population databases (gnomAD no frequency). 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). -

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	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;D;D;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;