NM_002382.4:c.184del is a frameshift variant predicted to result in a premature termination codon (p.Gln62LysfsTer3) in exon 4 of 5, with nonsense-mediated decay expected.1 Loss of function is an established disease mechanism for MAX, supported by germline disease association with polydactyly-macrocephaly syndrome (PMID:41203296).2 This variant meets PVS1 (very strong) under the ClinGen SVI generic framework (PMC6185798) as a null variant in a gene where LoF is a known mechanism of disease.3 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000 in all populations), meeting PM2 (moderate).4 No additional pathogenic criteria were met. PVS1 (very strong) + PM2 (moderate) is sufficient for a classification of Likely Pathogenic under generic ACMG/AMP 2015 rules (PMID:25741868).5
MAX
Final classification
Likely Pathogenic
MAX c.184del · p.Gln62LysfsTer3
MAX
NM_002382.4:c.184del is a frameshift variant predicted to result in a premature termination codon (p.Gln62LysfsTer3) in exon 4 of 5, with nonsense-mediated decay expected.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
MAX c.184del
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_variant_assessment
2
pvs1_gene_context
5
generic_acmg_combination_rules
Gene diagram
· NM_002382.4 · variants mapped to exon structure
MAX
NM_002382.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99408540, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 1 PMIDs triaged · 1 high-priority
1papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
24362264 ↗
functional
MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.
Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the swi
BS3PM1PS3
Sources & reference links