NM_002382.4:c.184delC

MAX · NP_002373.3:p.(Gln62LysfsTer3) · NM_002382.4

GRCh37: chr14:65544741 TG>T · GRCh38: chr14:65078023 TG>T

Gene: MAX Transcript: NM_002382.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

MAX

Transcript

NM_002382.4

Protein

NP_002373.3:p.(Gln62LysfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 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.
PS2	Not met	No de novo occurrence of NM_002382.4:c.184del with confirmed maternity and paternity has been reported in the literature or databases.
PS3	Not met	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.
PS4	Not met	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.
PS5	Not met	No reputable source has reported this variant as pathogenic with unavailable supporting evidence.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	MAX-associated disease is autosomal dominant; PM3 (detection in trans with a pathogenic variant) is not applicable for dominant disorders.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This is a frameshift deletion, not an in-frame change.
PM5	N/A	PM5 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.
PM6	Not met	No de novo occurrence of NM_002382.4:c.184del has been reported without confirmation of maternity and paternity.
PP1	Not met	No published family studies demonstrating co-segregation of NM_002382.4:c.184del with disease in multiple affected family members.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not met	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.
PP5	Not met	No reputable source has reported NM_002382.4:c.184del as pathogenic. The variant is absent from ClinVar in the structured pipeline output.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000). BA1 requires an allele frequency greater than 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0.000). BS1 requires an allele frequency greater than 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	The variant has not been observed in a healthy adult individual. BS2 requires observation in a healthy adult for a fully penetrant dominant disorder.
BS3	Not met	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.
BS4	Not met	No evidence of non-segregation with disease in affected families has been published for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant, not a missense substitution.
BP2	Not met	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.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This is a frameshift deletion, not an in-frame change.
BP4	Not met	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.	spliceai
BP5	Not met	This variant has not been observed in a case with an alternate molecular basis for disease. No such case report exists.
BP6	Not met	No reputable source has reported NM_002382.4:c.184del as benign.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant.

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