Variant classification summary

NM_000077.5:c.170C>G

CDKN2A · NP_000068.1:p.(Ala57Gly) · NM_000077.5

GRCh37: chr9:21971188 G>C · GRCh38: chr9:21971189 G>C

Gene: CDKN2A Transcript: NM_000077.5

Final call

VUS

BP4 supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.5

Protein

NP_000068.1:p.(Ala57Gly)

gnomAD AF

1.3770673223176293e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): REVEL 0.205 falls below the <0.250 threshold, predicting a benign effect.

2

Overall classification: VUS - one supporting benign criterion (BP4) is too weak to reach Likely Benign (requires 1 BS + 1 BP or 2 BP).

Final determination: Under the generic ACMG/AMP 2015 fallback combination rules (PMID:25741868), a single supporting benign criterion (BP4) with no other applied pathogenic or benign criterion meets none of the benign (BA1 alone or 2 BS), likely benign (1 BS + 1 BP or 2 BP), likely pathogenic, or pathogenic combination thresholds, and all other combinations are classified as Variant of Uncertain Significance.

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	N/A	Not applicable: this is a missense substitution, so no null-variant mechanism (nonsense-mediated decay, truncation, splice disruption) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to establish the identical amino acid change as pathogenic.
PS2	Not assessed	Not assessed: no proband-parent trio or parental-testing data document a de novo occurrence of this variant.
PS3	Not assessed	Not assessed: no well-established functional study tests this exact variant, and same-codon results for p.Ala57Val cannot substitute for p.Ala57Gly.	PMID:19260062 PMID:21462282
PS4	Not met	Not met: the variant was found in 1 of 420 healthy controls and in none of 388 melanoma patients, indicating no case enrichment.	PMID:22447455 PMID:21462282 clinvar
PM1	Not assessed	Not assessed: insufficient evidence was available to place p.Ala57Gly in a critical domain or mutational hotspot.
PM2	Not assessed	Not assessed: insufficient evidence was available on whether this variant is absent or extremely rare in population databases.
PM3	N/A	Not applicable: CDKN2A melanoma susceptibility is autosomal dominant, so the recessive in-trans requirement does not apply.	PMID:25741868 generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4 PMID:21462282 PMID:22447455
PM4	N/A	Not applicable: a missense substitution does not change protein length, leaving nothing for this length-change criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available on whether a different pathogenic missense affects this same codon.
PM6	Not assessed	Not assessed: no source reports a de novo occurrence of this variant, with or without confirmed parentage.
PP1	Not assessed	Not assessed: no co-segregation data exist; this variant was never observed in a familial-melanoma kindred.	PMID:21462282
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate missense variation burden in this gene.
PP3	Not met	Not met: REVEL 0.205 does not exceed the >0.750 PP3 threshold for predicted deleteriousness.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history was available to establish a highly specific presentation.
PP5	Not met	Not met: no ClinVar expert panel has classified this variant pathogenic or likely pathogenic (zero expert-panel submissions).	clinvar
BA1	Not assessed	Not assessed: insufficient evidence was available on population allele frequency.
BS1	Not assessed	Not assessed: insufficient evidence was available to compare allele frequency against that expected for the disorder.
BS2	Not assessed	Not assessed: insufficient evidence was available on observations of this variant in unaffected individuals.
BS3	Not assessed	Not assessed: no functional study tests this exact variant, and data for the different same-codon change p.Ala57Val cannot be extrapolated.	PMID:19260062 PMID:21462282
BS4	Not assessed	Not assessed: no family shows an affected relative who lacks the variant; a single unaffected control carrier is not non-segregation evidence.	PMID:22447455
BP1	Not assessed	Not assessed: insufficient evidence was available on whether CDKN2A-related disease arises only from truncating variants.
BP2	Not assessed	Not assessed: no observation places this variant in trans or in cis with a pathogenic CDKN2A variant.	PMID:25741868 generic_acmg_combination_rules clinvar PMID:21462282 PMID:22447455
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): REVEL 0.205 falls below the <0.250 BP4 threshold, predicting a benign effect.	revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no case-level data show an alternate molecular basis that explains the phenotype.
BP6	Not met	Not met: no ClinVar expert panel has classified this variant benign or likely benign (zero expert-panel submissions).	clinvar
BP7	N/A	Not applicable: c.170C>G is a missense, not a synonymous variant, so this silent-variant criterion cannot apply.	generic_acmg_combination_rules

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