Final classification

VUS

BP4

CDKN2A

c.170C>G

p.Ala57Gly

missense · exon 2

Gene context NCBI Gene ↗ OncoKB ↗

CDKN2A encodes two key proteins, p16(INK4a) and p14(ARF), that help control cell division. p16 blocks the cell cycle by inhibiting CDK4 and CDK6, preventing progression from the G1 to S phase, while p14 stabilizes the tumor suppressor p53 by preventing its degradation. CDKN2A is an important tumor suppressor: it is frequently mutated, deleted, or silenced in many cancers, including melanoma, lymphoma, and pancreatic and lung cancer, and inherited changes in the gene can predispose people to familial melanoma and pancreatic cancer.

This variant

Because inherited CDKN2A changes predispose to familial melanoma and pancreatic cancer, classifying this missense variant matters for cancer-risk management. c.170C>G (p.Ala57Gly) remains a VUS: the sole evidence is a benign in-silico prediction, with no functional, segregation, or de novo data to resolve its effect. It should not yet be treated as either benign or pathogenic when counseling carriers.

Transcript

NM_000077.5

HGVS · transcript:coding

NM_000077.5:c.170C>G

GRCh38

chr9:21971189 G>C

GRCh37

chr9:21971188 G>C

VUS: only BP4 (Supporting, REVEL 0.205 < 0.250) is met, and a single supporting benign criterion reaches neither Likely Benign nor Benign.

Classification rationale

BP4 VUS

CDKN2A c.170C>G missense · exon 2

BP4 (Supporting): REVEL 0.205 falls below the <0.250 threshold, predicting a benign effect. Overall classification: VUS - one supporting benign criterion (BP4) is too weak to reach Likely Benign (requires 1 BS + 1 BP or 2 BP).

BP4 → VUS

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.

Gene diagram · NM_000077.5 · variants mapped to exon structure

CDKN2A NM_000077.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 22 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

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

Governing framework: generic ACMG/AMP 2015 fallback (Richards et al., PMID:25741868) because no ClinGen CSPEC/VCEP or local custom CDKN2A specification exists in this case (cspec found=false; vcep_materials.json empty; gene_vcep_dir=null).Variant class: missense substitution NM_000077.5:c.170C>G, NP_000068.1:p.(Ala57Gly) (exon 2). Per the governing calibration (generic_acmg_combination_rules, output/generic_acmg_classification_rules.md, 'PP3/BP4 in-silico calibration (generic, non-VCEP only)'): missense variants use REVEL only; REVEL < 0.250 -> BP4 (supporting); REVEL in [0.250, 0.750] -> neither met.REVEL score 0.205 (source 'revel': local REVEL v1.3 lookup, chrom 9 pos 21971189 G>C). 0.205 < 0.250, therefore BP4 is met at supporting strength.

Assessed · not applied · 4 not met · 18 not assessed

Pathogenic

PS1 Not assessed: insufficient evidence was available to establish the identical amino acid change as pathogenic.

PS2 Not assessed: no proband-parent trio or parental-testing data document a de novo occurrence of this variant.

PS3 Not assessed: no well-established functional study tests this exact variant, and same-codon results for p.Ala57Val cannot substitute for p.Ala57Gly.

PS4 Not met: the variant was found in 1 of 420 healthy controls and in none of 388 melanoma patients, indicating no case enrichment.

PM1 Not assessed: insufficient evidence was available to place p.Ala57Gly in a critical domain or mutational hotspot.

PM2 Not assessed: insufficient evidence was available on whether this variant is absent or extremely rare in population databases.

PM5 Not assessed: insufficient evidence was available on whether a different pathogenic missense affects this same codon.

PM6 Not assessed: no source reports a de novo occurrence of this variant, with or without confirmed parentage.

PP1 Not assessed: no co-segregation data exist; this variant was never observed in a familial-melanoma kindred.

PP2 Not assessed: insufficient evidence was available to evaluate missense variation burden in this gene.

PP3 Not met: REVEL 0.205 does not exceed the >0.750 PP3 threshold for predicted deleteriousness.

PP4 Not assessed: no proband phenotype or family history was available to establish a highly specific presentation.

PP5 Not met: no ClinVar expert panel has classified this variant pathogenic or likely pathogenic (zero expert-panel submissions).

Benign

BA1 Not assessed: insufficient evidence was available on population allele frequency.

BS1 Not assessed: insufficient evidence was available to compare allele frequency against that expected for the disorder.

BS2 Not assessed: insufficient evidence was available on observations of this variant in unaffected individuals.

BS3 Not assessed: no functional study tests this exact variant, and data for the different same-codon change p.Ala57Val cannot be extrapolated.

BS4 Not assessed: no family shows an affected relative who lacks the variant; a single unaffected control carrier is not non-segregation evidence.

BP1 Not assessed: insufficient evidence was available on whether CDKN2A-related disease arises only from truncating variants.

BP2 Not assessed: no observation places this variant in trans or in cis with a pathogenic CDKN2A variant.

BP5 Not assessed: no case-level data show an alternate molecular basis that explains the phenotype.

BP6 Not met: no ClinVar expert panel has classified this variant benign or likely benign (zero expert-panel submissions).

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.37707e-05; MAF= 0.00138%, 22/1597598 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 2.00876e-05; MAF= 0.00201%, 1/49782 alleles, homozygotes = 0); grpmax FAF= 1.108e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.5781e-05; MAF= 0.00358%, 9/251530 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.87209e-05; MAF= 0.00787%, 9/114328 alleles, homozygotes = 0); grpmax FAF= 8.824e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0014% · 22 / 1,597,598
0 hom · FAF 0.0011%

European (Finnish) 1 / 49,782	0.002%
European (non-Finnish) 20 / 1,178,892	0.0017%
Remaining individuals 1 / 62,238	0.0016%

+ 7 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0036% · 9 / 251,530
0 hom · FAF 0.0088%

European (non-Finnish)

9 / 114,328

0.0079%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories). (ClinVarID = 187272)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.205. BayesDel score = -0.234048.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDKN2A, which encodes both a cyclin-dependent kinase inhibitor and an MDM2 inhibitor, is altered by mutation and deletion in various cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

Classifying variants of CDKN2A using computational and laboratory studies.

PMID 21462282 ↗ · Miller PJ et al. · 2011 Aug CLINVAR · functional

Searched

c.170C>Gp.(A57G)p.A57G

Found

The paper explicitly lists p.A57G (codon 57) once, in Table 1C (CDKN2A variants of uncertain significance): 0 familial-melanoma (FM) families, 1 carrier with multiple primary melanoma (MPM), 0 sporadic melanoma carriers, 0 nonmelanoma carriers, 1 total carrier. By the study's clinico-epidemiologic criteria it is therefore a VUS with no reported segregation with FM. The paper reports no functional (cell-cycle arrest), computational, or Bayesian integrated-analysis results specific to p.A57G; Table 3 (Bayesian classification) instead lists p.A57V, a different substitution at the same codon, classified as Class 3 uncertain (prior OR 1.25, neutral computational prediction 0.36, wild-type in vitro function 0.28, cumulative OR 0.13). Under the paper's rule that variants with only one line of evidence (computational) stay Class 3 uncertain, p.A57G is not reclassified. The paper also cautions generally that different variants at the same codon can have different functional outcomes.

Variant

✓ Names this variant — characterised directly

Applied to

→BP4 supporting

57 p.A57G 0 1 0 0 1

Location Table 1C (CDKN2A Variants of Uncertain Significance), codon 57 row · Context CDKN2A Mutation Database (NM_000077.2 reference, germline variants reported through February 2009); variants classified as VUS by clinico-epidemiologic criteria (found in a single individual etc.). p.A57G appears only in this database listing - no U2OS cell-cycle arrest assay, Bayesian integrated analysis, or in silico result is reported for it. · full text

Rule & framework references · cited for criterion definitions, not variant evidence

19260062 ↗ Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

15146471 ↗ Familial melanoma, pancreatic cancer and germline CDKN2A mutations. ONCOKB

22447455 ↗ MC1R, ASIP, TYR, and TYRP1 gene variants in a population-based series of multiple primary melanomas. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

29316957 ↗ Evaluating the breast cancer predisposition role of rare variants in genes associated with low-penetrance breast cancer risk SNPs. CLINVAR

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. CLINVAR

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