rs760147253
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2
The NM_002382.5(MAX):c.425C>T(p.Ser142Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,886 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S142P) has been classified as Uncertain significance.
Frequency
Consequence
NM_002382.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAX | NM_002382.5 | c.425C>T | p.Ser142Leu | missense_variant | 5/5 | ENST00000358664.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAX | ENST00000358664.9 | c.425C>T | p.Ser142Leu | missense_variant | 5/5 | 1 | NM_002382.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152048Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251486Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461838Hom.: 0 Cov.: 34 AF XY: 0.0000330 AC XY: 24AN XY: 727210
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74272
ClinVar
Submissions by phenotype
Pheochromocytoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 10, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2024 | The p.S142L variant (also known as c.425C>T), located in coding exon 5 of the MAX gene, results from a C to T substitution at nucleotide position 425. The serine at codon 142 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals with pheochromocytoma (Comino-Méndez I et al. Nat. Genet. 2011 Jun;43(7):663-7; Comino-Méndez I et al. J. Mol. Med., 2015 Nov;93:1247-55; Rattenberry E et al. J. Clin. Endocrinol. Metab., 2013 Jul;98:E1248-56). This alteration has also been detected in a cohort of 1336 renal cell carcinoma participants (Yngvadottir B et al. Hum Mol Genet, 2022 Aug;31:3001-3011). One functional assay using a luciferase reporter assay showed luciferase levels of p.S142L similar to wild-type MAX; another functional assay studied the regulation of MYC by MAX and showed that p.S142L did not affect this regulation (Comino-Méndez I et al. J. Mol. Med., 2015 Nov;93:1247-55). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 | Oct 27, 2022 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 142 of the MAX protein (p.Ser142Leu). This variant is present in population databases (rs760147253, gnomAD 0.01%). This missense change has been observed in individual(s) with pheochromocytomas and paragangliomas (PMID: 21685915, 23666964, 26269449). ClinVar contains an entry for this variant (Variation ID: 404109). 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. Experimental studies have shown that this missense change does not substantially affect 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at