About CDKN2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDKN2A c.124A>C, p.(Asn42His)
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: 1
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
This variant (p.Asn42His) is located at a residue within a statistically significant mutational hotspot as identified by CancerHotspots.org. Codon 42 lies within the first ankyrin repeat domain of p16INK4A, a critical functional domain for CDK4/CDK6 binding and cell cycle regulation.
PM2Moderate
PM2 · moderate
NM_001195132.1:c.124A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). This meets the PM2 threshold of allele frequency < 0.1% in population databases.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.03). BayesDel score is -0.0537, within the benign range. REVEL score is 0.441, in the indeterminate range and below the typical pathogenic threshold of 0.75. Together, these in silico predictions do not support a damaging effect.
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 moderate, PM2 moderate, BP4 supporting benign; combination = 2 moderate + 1 supporting benign, 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
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV58703253, n = 4 times).
Cancer Hotspots
This variant lies 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: 3 met · 17 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM1 is met at moderate strength: the variant (p.Asn42His) lies within a statistically significant mutational hotspot in CDKN2A, a critical functional domain for CDK4/CDK6 binding.
PM2 is met at moderate strength: NM_001195132.1:c.124A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency < 0.1%).
BP4 is met at supporting benign strength: multiple computational tools (SpliceAI max delta 0.03, BayesDel -0.0537, REVEL 0.441) do not support a deleterious effect on the gene product.
PVS1 is not met: the variant is a missense substitution (p.Asn42His), not a null variant eligible for PVS1 under the ClinGen SVI framework (PMC6185798).
PS1, PS2, PS3, PS4, PM6, PP1, PP2, PP3, PP4, PP5, BA1, BS1, BS2, BS3, BS4, and BP2 are not met: no variant-specific evidence meeting these criteria was identified in the literature, ClinVar, or population databases.
Overall classification: Uncertain Significance (VUS). Two moderate pathogenic criteria (PM1, PM2) and one supporting benign criterion (BP4) are met. This does not reach the Likely Pathogenic threshold (requires ≥3 moderate; or ≥2 moderate + ≥2 supporting; or ≥1 strong + ≥1 moderate) under generic ACMG/AMP 2015 combination rules (PMID:25741868).
No criteria match.
Met · 3
PM1 ModerateThis variant (p.Asn42His) is located at a residue within a statistically significant mutational hotspot as identified by CancerHotspots.org. Codon 42 lies within the first ankyrin repeat domain of p16INK4A, a critical functional domain for CDK4/CDK6 binding and cell cycle regulation. Details ▾Hide ▴
Evidence considered
- CancerHotspots.org identifies codon 42 as a statistically significant hotspot.
- Residue Asn42 lies within the ankyrin repeat domain of p16INK4A
- which mediates CDK4/CDK6 interaction.
PM2 ModerateNM_001195132.1:c.124A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). This meets the PM2 threshold of allele frequency < 0.1% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Still missing
- Coverage at this position in gnomAD was not explicitly confirmed
- though absence across multiple databases supports absence.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.03). BayesDel score is -0.0537, within the benign range. REVEL score is 0.441, in the indeterminate range and below the typical pathogenic threshold of 0.75. Together, these in silico predictions do not support a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.03 (no splicing impact).
- BayesDel: -0.0537 (benign).
- REVEL: 0.441 (indeterminate
- not damaging).
Sources
Not met · 17 · evaluated, threshold not reached
PVS1 This is a missense variant (NM_001195132.1:c.124A>C, p.Asn42His). The variant does not fall into the default generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per the ClinGen SVI PVS1 decision tree (PMC6185798), this variant is not eligible for PVS1 application. Details ▾Hide ▴
Evidence considered
- Missense variant (p.Asn42His) is not a null variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 No pathogenic or likely pathogenic variant at the same residue (p.Asn42) with a different nucleotide change has been identified. No same-residue comparators were recovered from ClinVar or the PM5 candidate search. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue candidates.
- ClinVar submission audit found no exact match for this variant on any transcript
- no comparators at residue Asn42.
Still missing
- No comprehensive screen for all possible nucleotide changes at codon 42 across all CDKN2A transcripts.
Sources
pm5_candidatesclinvar ↗
PS2 No de novo occurrence has been reported for NM_001195132.1:c.124A>C. No paper in the literature packet describes a de novo observation of this variant. Details ▾Hide ▴
Evidence considered
- No de novo evidence found in ClinVar submissions
- literature pass
- or publication queue.
Still missing
- No parental testing data available.
PS3 No well-established in vitro or in vivo functional studies have been identified for NM_001195132.1:c.124A>C (p.Asn42His). OncoKB classifies the variant as Likely Oncogenic in a somatic context, but this is a curated literature-based label, not primary functional evidence meeting PS3 standards for germline interpretation. Details ▾Hide ▴
Evidence considered
- OncoKB classifies as 'Likely Oncogenic' (somatic context only).
- No variant-specific functional assay data identified in literature.
Still missing
- No functional studies (e.g.
- cell cycle arrest assay
- CDK4/6 binding assay
- luciferase reporter) have been performed on this variant.
Sources
PS4 The prevalence of this variant in affected individuals has not been shown to be significantly increased compared to controls. The variant is absent from population databases, and no multiple unrelated probands with the same phenotype have been reported. The single ClinVar submission is from Ambry Genetics (VUS, single submitter) and does not provide case-level phenotype data. The one paper (PMID:25394175) is a practice guideline and contains no patient-specific variant data. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (no control data available for odds ratio).
- Single ClinVar submission (Ambry Genetics
- VUS
- single submitter) without matched phenotype data.
- No case reports or case series identified in literature.
Still missing
- No case-control study data.
- No proband counting data from clinical laboratories.
Sources
PM6 No de novo observation of NM_001195132.1:c.124A>C has been reported with confirmed maternity and paternity. No paper describes de novo occurrence of this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature.
Still missing
- No parental testing data available.
PP1 No segregation data are available for NM_001195132.1:c.124A>C. No family studies have been reported. Details ▾Hide ▴
Evidence considered
- No segregation analysis found in literature or ClinVar submissions.
Still missing
- No family-based cosegregation data.
PP2 PP2 requires a missense Z-score > 3.09 or equivalent evidence that the gene has a low rate of benign missense variation. HCI prior data is not available for CDKN2A, and no ClinGen-calibrated missense constraint metric was retrieved for this gene. Without quantitative constraint data, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior not found for CDKN2A.
- No missense Z-score or ClinGen constraint metric available in evidence packet.
Still missing
- Missense constraint metrics (e.g.
- gnomAD missense Z-score
- MTR
- MPC) were not precomputed for this gene.
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.441 (indeterminate, below the typical damaging threshold of >0.75). BayesDel score is -0.0537 (negative, favors benign). SpliceAI predicts no significant splice impact (max delta score = 0.03). Details ▾Hide ▴
Evidence considered
- REVEL: 0.441 (indeterminate).
- BayesDel: -0.0537 (benign range).
- SpliceAI max delta: 0.03 (no splicing impact).
Sources
PP4 No specific phenotype or clinical presentation has been reported for patients carrying NM_001195132.1:c.124A>C. The variant's phenotype specificity cannot be assessed without case-level clinical data. Details ▾Hide ▴
Evidence considered
- No case reports with detailed phenotype available.
- ClinVar submission does not include phenotypic data.
Still missing
- No phenotype data from probands.
PP5 No reputable source has classified NM_001195132.1:c.124A>C as pathogenic or likely pathogenic. The sole ClinVar entry (Variation ID 1795891) is classified as Uncertain Significance by Ambry Genetics (single submitter) and is not an exact match for this transcript — it corresponds to NM_000077.5:c.277A>C (p.Thr93Pro), a different CDKN2A isoform. The one associated paper (PMID:25394175) is an ACMG/NSGC practice guideline that does not mention this variant. Details ▾Hide ▴
Evidence considered
- ClinVar VUS (Ambry Genetics
- single submitter) — not an exact transcript match.
- PMID:25394175 is a general practice guideline
- not a variant-specific report.
Still missing
- No expert panel review of this variant.
Sources
BA1 NM_001195132.1:c.124A>C is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). The BA1 threshold of allele frequency > 1% is not met. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada.
Sources
BS1 NM_001195132.1:c.124A>C is absent from all population databases. The BS1 threshold of allele frequency > 0.3% is not met. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada.
Sources
BS2 No observation of NM_001195132.1:c.124A>C in a healthy adult individual has been reported. The variant is absent from gnomAD; no homozygous or heterozygous observations in unaffected controls are available. Details ▾Hide ▴
Evidence considered
- No observations in any population database.
- No reports of healthy adults carrying this variant.
BS3 No well-established in vitro or in vivo functional studies have demonstrated that NM_001195132.1:c.124A>C (p.Asn42His) has no damaging effect on protein function or splicing. Details ▾Hide ▴
Evidence considered
- No benign functional studies found in literature.
Still missing
- No functional studies of any kind have been performed on this variant.
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family-based segregation analysis.
BP2 No observation of NM_001195132.1:c.124A>C in trans with a known pathogenic CDKN2A variant has been reported. No phase data are available. Details ▾Hide ▴
Evidence considered
- No trans-phase observations reported.
Still missing
- No phase data available.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 applies to variants identified in trans with a pathogenic variant in recessive disorders. CDKN2A-associated disease (familial melanoma) is autosomal dominant; PM3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from non-repeat in-frame deletions/insertions or stop-loss variants. This is a missense substitution (p.Asn42His). Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic or likely pathogenic variant at the same residue (Asn42) with a different amino acid change has been identified in ClinVar. The PM5 candidate search returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 candidates at residue 42.
- No ClinVar entries for pathogenic missense variants at codon 42 of CDKN2A.
Sources
pm5_candidates
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. CDKN2A has both missense and truncating variants as established disease mechanisms in familial melanoma, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- CDKN2A loss of function is supported as a disease mechanism
- but missense variants are also a well-established disease mechanism in CDKN2A.
Sources
pvs1_gene_context
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ABP5 requires that the variant be found in a case with an alternate molecular basis for disease. No such evidence is available and this criterion is rarely applicable in practice for a variant with no case-level data. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source has classified NM_001195132.1:c.124A>C as benign or likely benign. The sole ClinVar submission is VUS, and it is not an exact match for this transcript. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing algorithms predict no impact. NM_001195132.1:c.124A>C is a missense variant (p.Asn42His), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion and no validated clinical framework in use for this case supports PS5 application. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CDKN2A
- Transcript
- NM_001195132.1
- Coding (HGVS c.)
- NM_001195132.1:c.124A>C
- Protein (HGVS p.)
- NP_001182061.1:p.(Asn42His)
- GRCh38
- chr9:21974704 T>G
- GRCh37
- chr9:21974703 T>G
- ClinVar
- 1795891
- COSMIC
- COSV58703253
Gene diagram
Every interpreted variant in CDKN2A, mapped onto the exon structure of NM_001195132.1. Select a row to find it on the plot.
CDKN2ANM_001195132.1
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
- 0.441
- BayesDel
- -0.054
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.03). BayesDel score is -0.0537, within the benign range. REVEL score is 0.441, in the indeterminate range and below the typical pathogenic threshold of 0.75. Together, these in silico predictions do not support a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.03 (no splicing impact).
- BayesDel: -0.0537 (benign).
- REVEL: 0.441 (indeterminate
- not damaging).
Sources
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.441 (indeterminate, below the typical damaging threshold of >0.75). BayesDel score is -0.0537 (negative, favors benign). SpliceAI predicts no significant splice impact (max delta score = 0.03). Details ▾Hide ▴
Evidence considered
- REVEL: 0.441 (indeterminate).
- BayesDel: -0.0537 (benign range).
- SpliceAI max delta: 0.03 (no splicing impact).
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing algorithms predict no impact. NM_001195132.1:c.124A>C is a missense variant (p.Asn42His), 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 = 0.03). REVEL score = 0.441. BayesDel score = -0.0537043.
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
-
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. · 2015ACMG/NSGC practice guideline providing referral criteria for cancer genetic consultation. Discusses CDKN2A in the context of familial melanoma (HM syndrome) referral criteria. The specific variant NM_001195132.1:c.124A>C was not mentioned in this paper.Does not name this variant
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 0.030
Open source ↗
ClinVar
1 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/?term=NM_001195132.1%3Ac.124A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-21974703-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-21974704-T-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-21974704-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001195132.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/CDKN2A/N42H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=174986157
- 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
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.441. BayesDel score = -0.0537043.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58703253, n = 4 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.