rs201743423

chr14-65102315-C-Achr14-65102315-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BS1_Supporting BS2

The NM_002382.5(MAX):c.25G>T(p.Val9Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: MAX NM_002382.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a chain Protein max (size 158) in uniprot entity MAX_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_002382.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.23076162).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000657 (10/152210) while in subpopulation NFE AF= 0.0000882 (6/68028). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAX	NM_002382.5	c.25G>T	p.Val9Leu	missense_variant	1/5	ENST00000358664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAX	ENST00000358664.9	c.25G>T	p.Val9Leu	missense_variant	1/5	1	NM_002382.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000890 AC: 22 AN: 247102 Hom.: 0 AF XY: 0.0000820 AC XY: 11 AN XY: 134146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000513

Gnomad NFE exome AF: 0.0000999

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461568 Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2023	Observed in an individual with bilateral pheochromocytoma, in another individual with both a paraganglioma and a pheochromocytoma in which loss of heterozygosity (LOH) was not detected and in a third individual with thyroid and breast cancer who also carried a deleterious MSH6 variant (Burnichon et al., 2012; Menara et al., 2015; Bakos et al., 2021); Published functional studies demonstrate inability to fully repress MYC activity compared to wildtype (Comino-Mendex et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22452945, 25405498, 34426522, 34130653, 26070438) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 13, 2017

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2023

The p.V9L variant (also known as c.25G>T), located in coding exon 1 of the MAX gene, results from a G to T substitution at nucleotide position 25. The valine at codon 9 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in a 13 year old male with a pheochromocytoma and a thoracoabdominal paraganglioma from a cohort of 1694 patients with pheochromocytoma or paraganglioma (Burnichon N et al. Clin. Cancer Res. 2012 May; 18(10):2828-37; Comino-Méndez I et al. J. Mol. Med. 2015 Nov; 93(11):1247-55). This alteration was also detected in a cohort of patients with co-occurring breast and thyroid cancer (Bakos B et al. BMC Cancer, 2021 Jun;21:706). Additionally, in a luciferase reporter assay, this alteration was found to have a minor impact on MYC’s E-box transcriptional activation (Comino-Méndez I et al. J. Mol. Med. 2015 Nov; 93(11):1247-55). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 9 of the MAX protein (p.Val9Leu). This variant is present in population databases (rs201743423, gnomAD 0.05%). This missense change has been observed in individual(s) with adrenal pheochromocytoma and thoracoabdominal paraganglioma (PMID: 22452945). ClinVar contains an entry for this variant (Variation ID: 313819). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt MAX function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MAX function (PMID: 26070438). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.96	D;D;.;T;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M;M;.;M;M;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.7	N;N;.;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.79
Sift	Benign	0.066	T;T;.;.;T;T;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;.;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.018, 0.99, 0.0	.;B;B;D;.;B;.;B;B;.;.;.
Vest4		0.41
MutPred		0.25		Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);Gain of catalytic residue at I7 (P = 0.0031);
MVP		0.81
MPC		0.98
ClinPred		0.57	D
GERP RS		4.8
Varity_R		0.72
gMVP		0.56

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: rs201743423; hg19: chr14-65569033;