About CDKN2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDKN2A c.322G>A, p.(Asp108Asn)
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
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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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
The exact variant (c.322G>A, p.Asp108Asn) was directly tested in functional assays by Huot et al. (2002, PMID:12417717). Co-immunoprecipitation experiments in patient-derived Q34 fibroblasts and recombinant expression in normal human diploid fibroblasts demonstrated significantly reduced binding of the Asp108Asn variant to both CDK4 and CDK6 (estimated at <5% of wild-type binding capacity in the compound heterozygous background, and markedly reduced relative to wild-type when expressed individually). Proliferation assays showed an intermediate reduction in cell cycle inhibitory function. The variant was classified as a 'partially impaired mutant.' Asp108 is structurally involved in stabilizing the hairpin loop between adjacent ankyrin-type repeats. A single study directly testing the exact variant with clear but partial functional impairment supports moderate-level PS3.
PM1Supporting
PM1 · supporting
The variant is located at a statistically significant hotspot residue (cancerhotspots.org) within the ankyrin repeat domain of p16INK4a, a functionally critical region for CDK4/CDK6 binding. The residue Asp108 is involved in stabilizing the hairpin loop between adjacent ankyrin-type repeats, and mutations in this domain are a well-established mechanism of CDKN2A pathogenicity.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and gnomAD-Canada, and is extremely rare in gnomAD v4.1 (2/1,606,056 alleles; AF = 0.000124%; highest subpopulation AF = 0.00133% in African/African American). The total allele frequency is well below the 0.1% threshold for PM2 application.
PP4Supporting
PP4 · supporting
The variant has been reported in a familial melanoma context. CDKN2A is an established melanoma susceptibility gene, and the patient phenotype (melanoma) is highly specific for CDKN2A-related disease. Orlow et al. (2007) identified c.322G>A (p.Asp108Asn) in an individual with melanoma noted under 'familial melanoma.' The variant was also identified in the Huot et al. (2002) proband who presented with melanoma in situ at age 23 and a second melanoma 5 years later, with a strong family history of cancer including melanoma in both parental lines.
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: PS3 moderate, PM1 supporting, PM2 supporting, PP4 supporting; combination = 1 moderate + 3 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
2 / 1,606,056 alleles
gnomAD v4.1: 2 / 1,606,056 alleles. Recorded AF 1.24529e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions
2 Uncertain significance · 1 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
35 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV58690777, n = 35 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: 4 met · 20 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001195132.1:c.322G>A (p.Asp108Asn) is a missense variant in exon 2 of CDKN2A, which encodes the p16INK4a tumor suppressor protein involved in G1 cell cycle regulation through CDK4/CDK6 inhibition.
Direct functional testing of the Asp108Asn variant by Huot et al. (2002) in patient-derived fibroblasts and recombinant expression systems demonstrated significantly reduced binding to both CDK4 and CDK6 and an intermediate reduction in cell cycle inhibitory function, classifying the variant as a partially impaired mutant (PS3_moderate).
The variant is located at a statistically significant hotspot residue within the ankyrin repeat domain of p16INK4a, a region critical for CDK4/CDK6 binding and tumor suppressor function (PM1_supporting).
The variant is absent from gnomAD v2.1 and gnomAD-Canada, and is extremely rare in gnomAD v4.1 (2/1,606,056 alleles, AF = 0.0001%), well below the 0.1% PM2 threshold (PM2_supporting).
The variant has been identified in a familial melanoma context: reported in the GEM population-based study in an individual with melanoma noted under familial melanoma, and in the Huot et al. proband who presented with melanoma in situ at age 23 with a second primary melanoma and a strong family history of cancer including melanoma in both parental lines (PP4_supporting).
Applying the ACMG/AMP 2015 generic combination rules: 1 moderate criterion (PS3) and 3 supporting criteria (PM1, PM2, PP4) are met. No benign criteria are met. The combination of 1 moderate + ≥2 supporting criteria satisfies the threshold for Likely Pathogenic classification.
No criteria match.
Met · 4
PS3 ModerateThe exact variant (c.322G>A, p.Asp108Asn) was directly tested in functional assays by Huot et al. (2002, PMID:12417717). Co-immunoprecipitation experiments in patient-derived Q34 fibroblasts and recombinant expression in normal human diploid fibroblasts demonstrated significantly reduced binding of the Asp108Asn variant to both CDK4 and CDK6 (estimated at <5% of wild-type binding capacity in the compound heterozygous background, and markedly reduced relative to wild-type when expressed individually). Proliferation assays showed an intermediate reduction in cell cycle inhibitory function. The variant was classified as a 'partially impaired mutant.' Asp108 is structurally involved in stabilizing the hairpin loop between adjacent ankyrin-type repeats. A single study directly testing the exact variant with clear but partial functional impairment supports moderate-level PS3. Details ▾Hide ▴
Evidence considered
- Co-immunoprecipitation: Asp108Asn variant showed significantly reduced binding to CDK4 and CDK6 relative to wild-type p16INK4a
- Proliferation assay: Asp108Asn produced an intermediate reduction in cell cycle inhibition (partially impaired)
- Structural context: Asp108 stabilizes the hairpin loop between adjacent ankyrin-type repeats
- mutation predicted to affect overall protein structure
Still missing
- Single study with partial impairment
- second independent functional study would strengthen to PS3_strong
Sources
PM1 SupportingThe variant is located at a statistically significant hotspot residue (cancerhotspots.org) within the ankyrin repeat domain of p16INK4a, a functionally critical region for CDK4/CDK6 binding. The residue Asp108 is involved in stabilizing the hairpin loop between adjacent ankyrin-type repeats, and mutations in this domain are a well-established mechanism of CDKN2A pathogenicity. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: statistically significant hotspot residue
- Ankyrin repeat domain (ankyrin III-IV): critical for CDK4/CDK6 binding and cell cycle regulation
- Structural role of Asp108 in hairpin loop stabilization between ankyrin repeats
Sources
PM2 SupportingThe variant is absent from gnomAD v2.1 and gnomAD-Canada, and is extremely rare in gnomAD v4.1 (2/1,606,056 alleles; AF = 0.000124%; highest subpopulation AF = 0.00133% in African/African American). The total allele frequency is well below the 0.1% threshold for PM2 application. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 2/1
- 606
- 056 alleles (0.000124%)
- 0 homozygotes
- gnomAD-Canada v1.0: absent
Sources
PP4 SupportingThe variant has been reported in a familial melanoma context. CDKN2A is an established melanoma susceptibility gene, and the patient phenotype (melanoma) is highly specific for CDKN2A-related disease. Orlow et al. (2007) identified c.322G>A (p.Asp108Asn) in an individual with melanoma noted under 'familial melanoma.' The variant was also identified in the Huot et al. (2002) proband who presented with melanoma in situ at age 23 and a second melanoma 5 years later, with a strong family history of cancer including melanoma in both parental lines. Details ▾Hide ▴
Evidence considered
- Identified in 1 familial melanoma case in GEM population-based study
- Huot 2002 proband: melanoma in situ at age 23
- second melanoma at 28
- strong family cancer history with melanoma in both parental lines
- CDKN2A is an established melanoma susceptibility gene with specific phenotype
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 108 (Asp) resulting in the same Asp108Asn amino acid substitution has been identified as a previously established pathogenic variant. Only c.322G>A has been reported at this position. Details ▾Hide ▴
Evidence considered
- Only c.322G>A reported at codon 108
- no alternative nucleotide change yielding D108N found in ClinVar or literature
Sources
PS2 No de novo occurrence data for NM_001195132.1:c.322G>A was identified in the reviewed literature or ClinVar submissions. No parentage testing confirming de novo status was available. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- No trio or parentage data available
PS4 The variant has been observed in only 1 individual with single primary melanoma (SPM) out of 2,424 SPM cases and 0 of 1,189 multiple primary melanoma (MPM) cases in the population-based GEM study (Orlow et al. 2007). These numbers are insufficient to meet PS4 thresholds for statistically significant enrichment in affected cases versus controls. Details ▾Hide ▴
Evidence considered
- 1 SPM case (0.04%)
- 0 MPM cases in GEM study
- insufficient case counts for PS4
Still missing
- Requires larger case-control studies or case counts for statistical enrichment
Sources
PM5 No confirmed pathogenic or likely pathogenic variant at the same residue (Asp108) with a different amino acid change was identified. The pm5_candidates module was unable to harvest same-residue comparator variants safely. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator variant identified at codon 108
Sources
pm5_candidates
PM6 No de novo occurrence data for this variant was identified in any reviewed publication or ClinVar submission. No confirmed de novo with maternity/paternity testing was available. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- No trio or parentage data available
PP1 Limited segregation data is available. The variant was noted to have been observed in a familial melanoma context (Orlow et al. 2007: 1 family), and one ClinVar submitter notes cosegregation in related individuals. However, another ClinVar submission notes that in one family two of four affected members did not carry the variant, indicating incomplete cosegregation. Insufficient robust segregation data to meet PP1. Details ▾Hide ▴
Evidence considered
- 1 familial melanoma family noted in GEM study (Orlow 2007)
- ClinVar: conflicting segregation signals — one submitter reports cosegregation
- another reports 2/4 affected members did not carry the variant
Still missing
- Formal segregation analysis (LOD scores) not available
- incomplete cosegregation reported
Sources
PP2 No gene-level missense constraint data (e.g., Z-score, missense depletion metrics) was available for CDKN2A to establish a low rate of benign missense variation. While CDKN2A is a known tumor suppressor with many pathogenic missense variants reported, specific constraint metrics needed for PP2 are absent. Details ▾Hide ▴
Evidence considered
- No CDKN2A missense constraint metrics available (HCI prior not supported for this gene)
Still missing
- Gene-level missense constraint data not available
PP3 In silico predictions are conflicting. REVEL score of 0.676 is above the 0.5 threshold supporting a deleterious prediction. However, BayesDel score of 0.034 is strongly benign-leaning. SpliceAI delta score is 0.00 indicating no splice impact. With only one tool supporting pathogenicity and another strongly contradicting it, the 'multiple lines of computational evidence' requirement for PP3 is not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL: 0.676 (deleterious)
- BayesDel: 0.034 (benign-leaning)
- SpliceAI max delta: 0.00 (no splice impact)
- HCI prior: not available
Sources
PP5 ClinVar classification for this variant is 'Uncertain significance' with review status 'criteria provided, single submitter' (1 star). The 3-star expert panel review threshold required for PP5 application is not met. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 1-star review status
- no 3-star expert panel classification available
Sources
BA1 The variant allele frequency in gnomAD v4.1 is 0.000124% (2/1,606,056 alleles), far below the 1% threshold for BA1. The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Maximum population AF = 0.00133% (African/African American)
- total AF = 0.000124% — well below 1% BA1 threshold
Sources
BS1 The variant allele frequency in gnomAD v4.1 is 0.000124% (2/1,606,056 alleles), far below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
- Maximum population AF = 0.00133% (African/African American)
- total AF = 0.000124% — well below 0.3% BS1 threshold
Sources
BS2 No evidence that this variant has been observed in healthy adult individuals in the absence of disease. The 2 alleles in gnomAD v4.1 are from an exome dataset without confirmatory phenotype data sufficient to establish healthy adult status. Details ▾Hide ▴
Evidence considered
- No confirmed observation in healthy adult controls
Still missing
- Population database observations lack phenotype confirmation
BS3 Functional studies by Huot et al. (2002, PMID:12417717) demonstrate a deleterious effect: significantly reduced CDK4/CDK6 binding and intermediate reduction in cell proliferation for the Asp108Asn variant. This is contradictory to BS3, which requires functional studies showing no damaging effect. Details ▾Hide ▴
Evidence considered
- Huot 2002: partial loss of function demonstrated — reduced Cdk binding and impaired cell cycle inhibition
Sources
BS4 No evidence of lack of segregation was identified. While one ClinVar submitter noted that in one family two of four affected members did not carry the variant, this observation alone is insufficient to meet BS4, which requires systematic non-segregation data. Details ▾Hide ▴
Evidence considered
- No systematic non-segregation data available
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. CDKN2A has numerous well-established pathogenic missense variants documented in the literature and ClinVar; missense changes are a recognized mechanism of pathogenicity in this gene. Details ▾Hide ▴
Evidence considered
- CDKN2A missense variants are a well-established disease mechanism
- numerous pathogenic missense variants in ClinVar and literature
Sources
BP2 No evidence that this variant has been observed in trans with a known pathogenic dominant variant in CDKN2A or any other gene. Details ▾Hide ▴
Evidence considered
- No observation in trans with pathogenic dominant variant
BP4 In silico evidence is conflicting. While BayesDel (0.034) leans benign, REVEL (0.676) predicts a deleterious effect. Multiple lines of computational evidence do not consistently support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.676 (deleterious — contradicts BP4)
- BayesDel: 0.034 (benign-leaning)
- SpliceAI: 0.00 (no splice impact)
Sources
BP5 No evidence that this variant was found in a case with an alternate molecular basis for disease. No alternative genetic diagnosis explaining the phenotype has been reported in carriers of this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis identified in variant carriers
BP6 ClinVar does not have a benign or likely benign classification for this variant from a 3-star expert panel. The only ClinVar entries are Uncertain significance (2 laboratories), Pathogenic (1 laboratory), and Likely pathogenic (1 laboratory), all at 1-star review level. Details ▾Hide ▴
PS5 No reputable source has recently reported this variant as definitively pathogenic with unavailable evidence. ClinVar classification is Uncertain significance (1-star review status), and the two submissions classifying as Pathogenic/Likely pathogenic are single-submitter clinical laboratories whose evidence is available for independent review. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- 1-star review status
- no external authoritative source with unavailable evidence
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001195132.1:c.322G>A is a missense variant (p.Asp108Asn) and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The pvs1_variant_assessment explicitly confirms the variant bucket is 'other' and generic PVS1 framework does not apply. Details ▾Hide ▴
Evidence considered
- Missense substitution at c.322G>A (p.D108N) in exon 2
- not a loss-of-function null variant
Sources
PM3 N/ATrivially not applicable: the variant is not observed in trans with a pathogenic variant for a recessive disorder (CDKN2A is associated with dominant melanoma predisposition). Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThe variant is a substitution, not a protein-length-altering change (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
No further detail was recorded.
BP3 N/AVariant is a substitution, not an in-frame indel in a non-repeat region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_001195132.1:c.322G>A is a missense variant (p.Asp108Asn), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous
Identifiers
- Gene
- CDKN2A
- Transcript
- NM_001195132.1
- Coding (HGVS c.)
- NM_001195132.1:c.322G>A
- Protein (HGVS p.)
- NP_001182061.1:p.(Asp108Asn)
- GRCh38
- chr9:21971037 C>T
- GRCh37
- chr9:21971036 C>T
- ClinVar
- 3265582, 216275
- COSMIC
- COSV58690777
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
2 / 1,606,056 alleles
AF 1.25e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,606,056 alleles · 0 hom
| African/African American1 / 75,020 | 1.3e-05 |
| European (non-Finnish)1 / 1,179,392 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24529e-06; MAF= 0.00012%, 2/1606056 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33298e-05; MAF= 0.00133%, 1/75020 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.676
- BayesDel
- 0.034
How the predictions were used
PP3 In silico predictions are conflicting. REVEL score of 0.676 is above the 0.5 threshold supporting a deleterious prediction. However, BayesDel score of 0.034 is strongly benign-leaning. SpliceAI delta score is 0.00 indicating no splice impact. With only one tool supporting pathogenicity and another strongly contradicting it, the 'multiple lines of computational evidence' requirement for PP3 is not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL: 0.676 (deleterious)
- BayesDel: 0.034 (benign-leaning)
- SpliceAI max delta: 0.00 (no splice impact)
- HCI prior: not available
Sources
BP4 In silico evidence is conflicting. While BayesDel (0.034) leans benign, REVEL (0.676) predicts a deleterious effect. Multiple lines of computational evidence do not consistently support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.676 (deleterious — contradicts BP4)
- BayesDel: 0.034 (benign-leaning)
- SpliceAI: 0.00 (no splice impact)
Sources
BP7 N/ANM_001195132.1:c.322G>A is a missense variant (p.Asp108Asn), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.676. BayesDel score = 0.0341573.
8 paper records listed. 2 cited in the classification.
Cited in the classification
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PMID 12417717 ↗Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts.Huot TJ et al. · 2002 DecThe c.322G>A (p.Asp108Asn) variant in CDKN2A was identified as one of two compound heterozygous missense mutations in the Q34 proband. Co-immunoprecipitation assays in patient-derived dermal fibroblasts and recombinant expression in normal HDFs demonstrated that the Asp108Asn variant has significantly reduced binding to both CDK4 and CDK6, with affinity markedly lower than wild-type p16INK4a. Proliferation assays showed an intermediate reduction in cell cycle inhibitory function, classifying Asp108Asn as a partially impaired mutant. Asp108 is structurally involved in stabilizing the hairpin loop between adjacent ankyrin-type repeats.→ PS3 → PM1 → PP4 Names this variant
Source detail
G to A at nucleotide 322, which changes Asp to Asn at residue 108 of p16INK4a
Location Results (pages 8136-8137): lines 208-213 describe the mutation; Figure 2C shows Cdk immunoprecipitation data; Figure 2D shows proliferation assay; Discussion (pages 8140-8141): lines 609-618 discuss Asp108Asn variant
Context Co-immunoprecipitation of endogenous p16INK4a with Cdk4/Cdk6 in Q34 patient dermal fibroblasts; retroviral expression of HA-tagged Asp108Asn in normal human diploid fibroblasts (Hs68 and 904); cell proliferation assay over 10 days
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PMID 17218939 ↗CDKN2A germline mutations in individuals with cutaneous malignant melanoma.Orlow I et al. · 2007 MayThe c.322G>A (p.Asp108Asn) variant was identified in 1 of 2,424 individuals with single primary melanoma (0.04%) and 0 of 1,189 individuals with multiple primary melanoma in the population-based GEM study. One first-degree relative with melanoma was reported. The variant was noted as previously identified in 1 familial melanoma family. Existing in vitro data at the time (Koh 1995, Ranade 1995, Reymond 1995) was classified as showing no change from wild type; however, subsequent studies (Huot 2002, PMID:12417717) demonstrated partial functional impairment.→ PP4 Names this variant
Source detail
c.322 G>A Asp108Asn Arg163Gln No change 1 (0.04) 0 1/2 1 family
Location Table 1, rows for c.322G>A and c.306G>A+c.322G>A; Results section
Context Population-based case-control study (GEM): denaturing HPLC screening followed by Sanger sequencing of exons 1a, 2, and 3 of CDKN2A
Other recorded publications
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PMID 16896043 ↗The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study.Berwick M et al. · 2006Population-based study of CDKN2A germline mutations and melanoma risk in the GEM cohort. Reported 32 different functional mutations across 63 participants but did not list individual variants. The specific c.322G>A (p.Asp108Asn) variant was not identified or discussed in this publication.Does not name this variant
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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. · 2006GenoMEL consortium study of 466 melanoma families characterizing mutations in CDKN2A, CDK4, and ARF across 17 centers worldwide. Reported 57 distinct CDKN2A mutations across 178 families. The specific c.322G>A (p.Asp108Asn) variant was not identified among the catalogued mutations in this study.Does not name this variant
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PMID 21462282 ↗Classifying variants of CDKN2A using computational and laboratory studies.Miller PJ et al. · 2011Study on classifying CDKN2A variants using computational and laboratory methods (Miller et al. 2011). Full text was not available (only a PNG figure was retrieved). Abstract does not mention the specific c.322G>A variant. The paper focuses broadly on methods for variant classification rather than specific variant testing.Does not name this variant
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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.ACMG/AMP standards and guidelines for sequence variant interpretation (Richards et al. 2015). This is a methodological framework publication that does not discuss any specific CDKN2A variants. Used as the classification combination rule reference only.Does not name this variant
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PMID 29091774 ↗Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System.Hallett ST et al. · 2017Study of differential regulation of G1 CDK complexes by the Hsp90-Cdc37 chaperone system. Focused on CDK4/CDK6 kinase-chaperone interactions at the biochemical level. CDKN2A and the c.322G>A variant were not mentioned in this paper.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,606,056 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance · 1 Pathogenic · 1 Likely pathogenic
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/216275/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-21971036-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-21971037-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-21971037-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001195132.1%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/CDKN2A/D108N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=174979967
- 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
This variant is present in gnomAD v4.1 (AF= 1.24529e-06; MAF= 0.00012%, 2/1606056 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33298e-05; MAF= 0.00133%, 1/75020 alleles, homozygotes = 0).
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) and as Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 216275)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.676. BayesDel score = 0.0341573.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58690777, n = 35 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.