About CDKN2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDKN2A c.151G>T, p.(Val51Phe)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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
PM1Supporting
PM1 · supporting
The variant is located at codon 51 within the first ankyrin repeat domain of p16INK4A (residues ~34-76), a well-established critical functional domain required for CDK4/6 binding and cyclin-dependent kinase inhibition. This region is a known mutational hotspot in familial melanoma, and many pathogenic missense variants cluster in the ankyrin repeats.
PM2Supporting
PM2 · supporting
The variant is absent from all large population databases including gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles), consistent with a rare variant that may be associated with disease.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105891454, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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 · 18 not met · 3 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000077.4:c.151G>T (p.Val51Phe) is a missense variant in exon 2 of CDKN2A, located in the first ankyrin repeat domain critical for CDK4/6 binding and cyclin-dependent kinase inhibition.
PM1 (supporting): The variant lies at codon 51 within ankyrin repeat 1, a well-established mutational hotspot and critical functional domain where many pathogenic missense variants cluster in familial melanoma.
PM2 (supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele count 0), consistent with a rare variant.
PVS1 is not applicable as this is a missense variant that does not fall into any null-variant bucket per the ClinGen SVI PVS1 decision tree (PMC6185798).
In silico predictions are conflicting: REVEL score 0.561 suggests a damaging effect, while BayesDel 0.137 (benign range) and SpliceAI max delta 0.02 (no splice impact) do not support pathogenicity. Neither PP3 nor BP4 can be applied due to discordant computational evidence.
No functional studies directly testing p.V51F, no cosegregation data, no de novo reports, and no case-control data were identified in the reviewed literature. ClinVar submissions from two clinical laboratories classify this variant as Uncertain significance.
Based on generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting pathogenic criteria (PM1_Supporting + PM2_Supporting) in the absence of any benign criteria is insufficient to reach Likely Pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM1 SupportingThe variant is located at codon 51 within the first ankyrin repeat domain of p16INK4A (residues ~34-76), a well-established critical functional domain required for CDK4/6 binding and cyclin-dependent kinase inhibition. This region is a known mutational hotspot in familial melanoma, and many pathogenic missense variants cluster in the ankyrin repeats. Details ▾Hide ▴
Evidence considered
- Codon 51 lies in ankyrin repeat 1
- a critical CDK4/6-binding domain
- multiple pathogenic missense variants map to this region in melanoma
Still missing
- CDKN2A-specific VCEP domain boundaries for PM1 are not available
- generic ACMG domain-level assessment was used
Sources
PM2 SupportingThe variant is absent from all large population databases including gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles), consistent with a rare variant that may be associated with disease. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AC=0)
- gnomAD v4.1 (AC=0)
- gnomAD-Canada v1.0 (AC=0)
- allele frequency below PM2 threshold of 0.1%
Sources
Not met · 18 · evaluated, threshold not reached
PS2 PS2 requires a de novo occurrence with confirmed maternity and paternity. No de novo observation of c.151G>T in CDKN2A has been reported in the literature, ClinVar submissions, or public databases. Details ▾Hide ▴
Evidence considered
- Exploratory literature search found no de novo reports for p.V51F
Still missing
- De novo reports are rare for adult-onset cancer syndromes such as familial melanoma
- dedicated trio studies would be required
PS3 PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No published functional assay directly testing p.V51F (e.g., CDK4/6 binding, cell-cycle arrest, subcellular localization) was identified. The variant lies in the first ankyrin repeat domain, which is functionally critical for CDK4/6 inhibition, but variant-specific functional data are absent. Details ▾Hide ▴
Evidence considered
- OncoKB reports no variant-specific functional evidence
- exploratory search found only indirect gene-level functional context for residues near Val51
Still missing
- Dedicated functional study of p.V51F (CDK4 binding assay
- cell-cycle arrest
- pRB phosphorylation) is needed to resolve this criterion
Sources
PS4 PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls. No case-control study has been published for p.V51F. Three ClinVar submitters classify it as Uncertain significance, but no proband counts with odds ratios are available. The variant's absence from gnomAD supports rarity (PM2) but does not independently satisfy PS4 prevalence requirements. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
- ClinVar submissions from 2 clinical laboratories classify as VUS
- no published case-control data
Still missing
- Aggregated case counts from testing laboratories or a formal case-control study are needed
Sources
PM6 PM6 requires a de novo observation with confirmed parental relationships. No de novo report of c.151G>T has been identified in the literature, databases, or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo occurrence with confirmed paternity/maternity reported
Still missing
- De novo mutations in CDKN2A are rare and typically not investigated for adult-onset cancer predisposition
PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members. No published cosegregation data for p.V51F in melanoma-prone families was identified. Details ▾Hide ▴
Evidence considered
- No published cosegregation analysis for this variant identified
Still missing
- Cosegregation data from melanoma family studies (e.g.
- GenoMEL consortium) may exist but was not identified in abstracts or full-text review
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. In silico predictions are conflicting: REVEL score 0.561 supports a damaging effect, but BayesDel score 0.137 (below the ~0.27 damaging threshold) and SpliceAI max delta 0.02 (no predicted splice impact) do not support pathogenicity. The computational evidence is not consistently deleterious; REVEL alone does not constitute 'multiple lines.' Details ▾Hide ▴
Evidence considered
- REVEL=0.561 (damaging)
- BayesDel=0.137 (benign-range)
- SpliceAI max delta=0.02 (no splice impact)
Sources
PP4 PP4 requires that the patient's phenotype or family history is highly specific for the disease. No individual-level phenotypic data for probands carrying this variant has been reported in the available literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No proband-level phenotype data available in ClinVar submissions or literature
Still missing
- Detailed clinical phenotypes of carriers would be needed to assess disease specificity
PP5 PP5 requires a reputable source (e.g., clinical diagnostic laboratory with expertise in the disease) to have classified the variant as pathogenic. All three ClinVar submissions classify c.151G>T as Uncertain significance; none report Pathogenic or Likely Pathogenic. PP5 is therefore not satisfied. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 clinical laboratories classify as VUS
- no submitter reports Pathogenic or Likely Pathogenic
Sources
BA1 BA1 requires an allele frequency >1% in any population database. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele count 0, allele frequency 0.0). Far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- AF=0.0 in all population databases
- BA1 threshold is >1%
Sources
BS1 BS1 requires an allele frequency >0.3% in population databases for a dominant disorder. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0). Far below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- AF=0.0
- BS1 threshold for dominant disorders is >0.3%
Sources
BS2 BS2 requires observation of the variant in a healthy adult individual, or in homozygous state without disease. No such observation has been reported for c.151G>T. Details ▾Hide ▴
Evidence considered
- No reported observation in healthy adults or homozygous state
Still missing
- Population screening or incidentalome data could reveal healthy carriers
BS3 BS3 requires well-established functional studies demonstrating no damaging effect. No functional assay directly testing p.V51F has been published. The variant lies in the functionally critical ankyrin repeat domain, where many substitutions impair CDK4/6 binding; a benign functional outcome for V51F should not be assumed without direct evidence. Details ▾Hide ▴
Evidence considered
- No functional studies of p.V51F identified
- OncoKB reports no variant-specific functional evidence
Still missing
- Functional characterization of p.V51F (CDK4 binding assay) would be required to meet BS3
BS4 BS4 requires lack of segregation with disease in multiple affected family members. No segregation data (positive or negative) has been published for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available for this variant
Still missing
- Segregation analysis in melanoma families would be needed
BP1 BP1 applies when a missense variant is found in a gene where only truncating variants are known to cause disease. CDKN2A-associated familial melanoma can be caused by both missense and truncating variants; missense changes in the ankyrin repeat domains are a well-established pathogenic mechanism. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- CDKN2A disease is caused by both missense and truncating variants
- BP1 does not apply
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant for a fully penetrant dominant disorder, without clinical consequences. No such observation has been reported for p.V51F. Details ▾Hide ▴
Evidence considered
- No reported observation in trans with a pathogenic CDKN2A variant
Still missing
- Cases with biallelic CDKN2A variants are extremely rare and have not been reported for this variant
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. In silico predictions are conflicting: BayesDel 0.137 (benign range) and SpliceAI 0.02 (no splice impact) suggest no effect, but REVEL 0.561 predicts a damaging effect. The discordance between tools precludes application of BP4 under standard ACMG/AMP guidance. Details ▾Hide ▴
Evidence considered
- REVEL=0.561 (damaging) conflicts with BayesDel=0.137 (benign) and SpliceAI=0.02 (neutral)
- conflicting predictions preclude BP4
Sources
BP5 BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such case has been reported for c.151G>T. Details ▾Hide ▴
Evidence considered
- No reported co-occurrence with a confirmed pathogenic variant in an alternate melanoma-predisposition gene
Still missing
- Co-occurrence data from multi-gene panel testing may exist in clinical laboratory databases
BP6 BP6 requires a reputable source to classify the variant as Benign or Likely Benign. All ClinVar submissions classify c.151G>T as Uncertain significance; no submitter reports a benign classification. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 clinical laboratories classify as VUS
- no benign or likely benign classifications
Sources
Not assessed · 3 · no assessment recorded
PS1 PS1 requires a different nucleotide change at the same position that is a known pathogenic variant. The PM5 candidate search found no comparator variants at codon 51 with established pathogenicity; no same-residue pathogenic comparator could be identified. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned zero same-residue comparator variants with known pathogenicity
Still missing
- A comprehensive literature search for pathogenic variants at codon 51 (e.g.
- V51A
- V51L) is needed
Sources
pm5_candidates
PP2 PP2 applies when a gene has a low rate of benign missense variation and missense variants are a common disease mechanism. CDKN2A is a tumor suppressor with missense variants as a known disease mechanism. However, without CSPEC/VCEP-defined missense constraint metrics (z-score, HCI prior) for CDKN2A, PP2 cannot be reliably applied in the generic ACMG framework. Details ▾Hide ▴
Evidence considered
- CDKN2A missense constraint data (HCI prior) is not available for this gene
Still missing
- CDKN2A missense constraint metrics (e.g.
- gnomAD missense z-score
- HCI prior probability) are needed to apply PP2
PS5 PS5 is not a valid ACMG/AMP 2015 criterion. PS5 was retired from the original nomenclature; PM5 covers same-residue alternate pathogenic changes. See PM5 assessment. Details ▾Hide ▴
Evidence considered
- PS5 is obsolete
- same-residue comparator logic is covered under PM5
Sources
pm5_candidates
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). NM_000077.4:c.151G>T is a missense variant (p.Val51Phe) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 51
- variant bucket 'other' — not eligible for PVS1
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders. CDKN2A-associated familial melanoma is autosomal dominant. Skipped per case instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This is a missense substitution. Skipped per case instructions. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a different amino acid change at the same residue that has been classified as pathogenic. The automated PM5 candidate search found zero same-residue comparator variants in ClinVar with pathogenic or likely pathogenic classification. Classic PM5 semantics cannot be applied. Details ▾Hide ▴
Evidence considered
- No pathogenic/likely pathogenic comparator variants identified at codon 51
Still missing
- Manual literature search for pathogenic variants at codon 51 (e.g.
- V51A
- V51D) may identify comparators
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame indels in repetitive regions without a known function. Skipped per case instructions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants where splicing algorithms predict no impact and the nucleotide is not highly conserved. NM_000077.4:c.151G>T is a missense variant (p.Val51Phe), not a synonymous change. BP7 is reserved for synonymous/intronic variants that do not alter the amino acid sequence. Details ▾Hide ▴
Evidence considered
- Missense variant (p.Val51Phe)
- BP7 is applicable only to synonymous variants
Sources
Identifiers
- Gene
- CDKN2A
- Transcript
- NM_000077.4
- Coding (HGVS c.)
- NM_000077.4:c.151G>T
- Protein (HGVS p.)
- NP_000068.1:p.(Val51Phe)
- GRCh38
- chr9:21971208 C>A
- GRCh37
- chr9:21971207 C>A
- ClinVar
- 3641072, 2735266, 1177438
- COSMIC
- COSV105891454
Gene diagram
Every interpreted variant in CDKN2A, mapped onto the exon structure of NM_000077.4. Select a row to find it on the plot.
CDKN2ANM_000077.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CDKN2A
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.561
- BayesDel
- 0.137
How the predictions were used
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. In silico predictions are conflicting: REVEL score 0.561 supports a damaging effect, but BayesDel score 0.137 (below the ~0.27 damaging threshold) and SpliceAI max delta 0.02 (no predicted splice impact) do not support pathogenicity. The computational evidence is not consistently deleterious; REVEL alone does not constitute 'multiple lines.' Details ▾Hide ▴
Evidence considered
- REVEL=0.561 (damaging)
- BayesDel=0.137 (benign-range)
- SpliceAI max delta=0.02 (no splice impact)
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. In silico predictions are conflicting: BayesDel 0.137 (benign range) and SpliceAI 0.02 (no splice impact) suggest no effect, but REVEL 0.561 predicts a damaging effect. The discordance between tools precludes application of BP4 under standard ACMG/AMP guidance. Details ▾Hide ▴
Evidence considered
- REVEL=0.561 (damaging) conflicts with BayesDel=0.137 (benign) and SpliceAI=0.02 (neutral)
- conflicting predictions preclude BP4
Sources
BP7 N/ABP7 applies to synonymous (silent) variants where splicing algorithms predict no impact and the nucleotide is not highly conserved. NM_000077.4:c.151G>T is a missense variant (p.Val51Phe), not a synonymous change. BP7 is reserved for synonymous/intronic variants that do not alter the amino acid sequence. Details ▾Hide ▴
Evidence considered
- Missense variant (p.Val51Phe)
- BP7 is applicable only to synonymous variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.561. BayesDel score = 0.136755.
9 paper records 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
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PMID 17047042 ↗High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.Goldstein AM et al. · 2006No paper-specific finding is recorded.
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PMID 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.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 31672839 ↗Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.Goggins M et al. · 2020No paper-specific finding is recorded.
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PMID 7987388 ↗Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.Kamb A et al. · 1994No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 40674536 ↗CDKN2A Cancer Predisposition.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
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 0.020
Open source ↗
ClinVar
2 Uncertain significance
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2735266/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-21971207-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-21971208-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-21971208-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000077.4%3Ac.151G…
- OncoKB ↗www.oncokb.org/gene/CDKN2A/V51F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=175008912
- Cancer hotspots ↗www.cancerhotspots.org/
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 2735266)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.561. BayesDel score = 0.136755.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105891454, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.