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MAXc.184delLikely pathogenic
Print report
Variant interpretation report

MAX c.184del, p.(Gln62LysfsTer3)

NM_002382.4:c.184del NP_002373.3:p.(Gln62LysfsTer3) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MAX

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_002382.4:c.184del is a frameshift variant predicted to produce a premature termination codon at amino acid 62 (p.Gln62LysfsTer3) in exon 4 of 5, well upstream of the NMD boundary. Loss of function is an established disease mechanism for MAX, supported by germline disease association including polydactyly-macrocephaly syndrome (PMID:41203296). Under the ClinGen SVI PVS1 recommendations (PMC6185798), this null variant in a gene with established LoF mechanism meets PVS1 at full strength.

PM2Moderate
PM2 · moderate

NM_002382.4:c.184del is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000 in all populations), meeting the PM2 threshold of <0.1% for a variant with no population frequency data.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99408540, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 19 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Loss of function is an established disease mechanism for MAX, supported by germline disease association with polydactyly-macrocephaly syndrome (PMID:41203296).

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.

The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000 in all populations), meeting PM2 (moderate).

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).

Met · 2

PVS1 Very strongNM_002382.4:c.184del is a frameshift variant predicted to produce a premature termination codon at amino acid 62 (p.Gln62LysfsTer3) in exon 4 of 5, well upstream of the NMD boundary. Loss of function is an established disease mechanism for MAX, supported by germline disease association including polydactyly-macrocephaly syndrome (PMID:41203296). Under the ClinGen SVI PVS1 recommendations (PMC6185798), this null variant in a gene with established LoF mechanism meets PVS1 at full strength. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion NM_002382.4:c.184del (p.Gln62LysfsTer3) in exon 4/5
  • Premature termination codon predicted to trigger nonsense-mediated decay
  • Loss of function is established disease mechanism for MAX
  • MAX germline disease association confirmed by PMID:41203296 (polydactyly-macrocephaly syndrome)
Still missing
  • No CSPEC/VCEP-specific PVS1 decision tree for MAX
  • applied generic PMC6185798 framework
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment41203296
PM2 ModerateNM_002382.4:c.184del is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000 in all populations), meeting the PM2 threshold of <0.1% for a variant with no population frequency data. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 19 · evaluated, threshold not reached

PS2 No de novo occurrence of NM_002382.4:c.184del with confirmed maternity and paternity has been reported in the literature or databases. Details ▾Hide ▴
Still missing
  • No de novo case reports identified in PubMed or ClinVar for this variant
PS3 No variant-specific functional studies demonstrating a deleterious effect have been identified. PMID:24362264 discusses MAX inactivation in small cell lung cancer at the gene level but does not mention the specific variant NM_002382.4:c.184del. Details ▾Hide ▴
Evidence considered
  • PMID:24362264 discusses MAX inactivation in SCLC at gene level
  • not variant-specific
Still missing
  • No variant-specific functional assay data available for NM_002382.4:c.184del
Sources
24362264
PS4 No formal case-control study or statistically significant enrichment of this variant in affected individuals versus controls has been published. While an exploratory search suggested a ClinVar entry (VCV000233767) with pathogenic classifications, the structured ClinVar pipeline did not confirm an exact match, and no aggregated proband count with odds ratio is available. Absence from gnomAD is applied under PM2. Details ▾Hide ▴
Evidence considered
  • Exploratory search identified a possible ClinVar entry (VCV000233767) but structured pipeline found no exact ClinVar match
Still missing
  • Discrepancy between exploratory ClinVar finding and structured evidence_brief (ClinVar absent). Recommend manual ClinVar review.
  • No case-control odds ratio or statistical enrichment data available
PM1 This variant does not lie in a statistically significant mutational hotspot (Cancer Hotspots negative). While the bHLH-Zip domain of MAX is functionally critical, PM1 requires a well-established domain with absence of benign variation, which has not been formally curated for MAX under a VCEP framework. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no significant hotspot at this residue
Still missing
  • No VCEP-defined critical domain for MAX
  • PM1 requires formal domain-level curation
PM6 No de novo occurrence of NM_002382.4:c.184del has been reported without confirmation of maternity and paternity. Details ▾Hide ▴
Still missing
  • No assumed de novo case reports in the literature
PP1 No published family studies demonstrating co-segregation of NM_002382.4:c.184del with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No co-segregation data available
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score 0.00). REVEL and BayesDel are not applicable (not a single-nucleotide substitution). HCI Prior is not available for MAX. No in silico evidence is available to support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.00 (no predicted splice impact)
  • REVEL not applicable (not SNV)
  • BayesDel not applicable (not SNV)
  • HCI Prior not found for MAX
Sources
spliceai ↗
PP4 No patient-specific phenotype or family history data are available for independent assessment. PP4 requires that the proband's phenotype is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • No proband phenotype data provided
PP5 No reputable source has reported NM_002382.4:c.184del as pathogenic. The variant is absent from ClinVar in the structured pipeline output. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000). BA1 requires an allele frequency greater than 1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.000 in gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000). BS1 requires an allele frequency greater than 0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.000 in gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 The variant has not been observed in a healthy adult individual. BS2 requires observation in a healthy adult for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
  • No observation in healthy adult controls beyond gnomAD
BS3 No well-established functional studies demonstrate a benign effect for this variant. PMID:24362264 discusses MAX inactivation (loss of function) in small cell lung cancer at the gene level, which is consistent with a deleterious rather than benign mechanism. Details ▾Hide ▴
Evidence considered
  • PMID:24362264 shows MAX inactivation in SCLC consistent with LoF
  • not benign
Still missing
  • No variant-specific functional assay demonstrating no deleterious effect
Sources
24362264
BS4 No evidence of non-segregation with disease in affected families has been published for this variant. Details ▾Hide ▴
Still missing
  • No segregation or non-segregation data available
BP2 NM_002382.4:c.184del has not been observed in trans with a known pathogenic MAX variant or in cis with a pathogenic variant for a recessive disorder. MAX-associated disease is autosomal dominant, and no such co-occurrence has been reported. Details ▾Hide ▴
Still missing
  • No observation in trans with a pathogenic MAX variant
BP4 Multiple lines of computational evidence do not suggest a benign impact. SpliceAI predicts no splice alteration (max delta 0.00), but REVEL and BayesDel are not applicable to this deletion variant. The frameshift nature of the variant is inherently disruptive, and no computational evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00 (no splice impact)
  • REVEL/BayesDel not applicable (not SNV)
  • Frameshift variant inherently protein-truncating
Sources
spliceai ↗
BP5 This variant has not been observed in a case with an alternate molecular basis for disease. No such case report exists. Details ▾Hide ▴
Still missing
  • No observation in a case with alternative molecular diagnosis
BP6 No reputable source has reported NM_002382.4:c.184del as benign. Details ▾Hide ▴

No further detail was recorded.

PS5 No reputable source has reported this variant as pathogenic with unavailable supporting evidence. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when a different nucleotide change at the same position has been established as pathogenic. This is a single-base deletion, not a substitution. No applicable same-position nucleotide change comparator exists. Details ▾Hide ▴

No further detail was recorded.

PM3 N/AMAX-associated disease is autosomal dominant; PM3 (detection in trans with a pathogenic variant) is not applicable for dominant disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This is a frameshift deletion, not an in-frame change. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to novel missense variants at the same amino acid residue as a known pathogenic missense change. This is a frameshift variant, not a missense substitution. No same-residue missense comparator is applicable. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This variant is a frameshift deletion, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. This is a frameshift deletion, not an in-frame change. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
MAX
Transcript
NM_002382.4
Coding (HGVS c.)
NM_002382.4:c.184del
Protein (HGVS p.)
NP_002373.3:p.(Gln62LysfsTer3)
GRCh38
chr14:65078023 TG>T
GRCh37
chr14:65544741 TG>T
COSMIC
COSV99408540

Gene diagram

Every interpreted variant in MAX, mapped onto the exon structure of NM_002382.4. Select a row to find it on the plot.

MAXNM_002382.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score 0.00). REVEL and BayesDel are not applicable (not a single-nucleotide substitution). HCI Prior is not available for MAX. No in silico evidence is available to support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.00 (no predicted splice impact)
  • REVEL not applicable (not SNV)
  • BayesDel not applicable (not SNV)
  • HCI Prior not found for MAX
Sources
spliceai ↗
BP4 Multiple lines of computational evidence do not suggest a benign impact. SpliceAI predicts no splice alteration (max delta 0.00), but REVEL and BayesDel are not applicable to this deletion variant. The frameshift nature of the variant is inherently disruptive, and no computational evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00 (no splice impact)
  • REVEL/BayesDel not applicable (not SNV)
  • Frameshift variant inherently protein-truncating
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.
    Reports tumor-specific inactivation of MAX in small cell lung cancer, demonstrating that MAX loss disrupts MYC-SWI/SNF transcriptional programs and is synthetic lethal with BRG1. The variant NM_002382.4:c.184del was not identified in this paper.
    Does not name this variant
    PMID 24362264 ↗
    Quoted passage
    Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99408540, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.