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CDK6c.197G>AUncertain significance
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Variant interpretation report

CDK6 c.197G>A, p.(Arg66Lys)

NM_001259.8:c.197G>A NP_001250.1:p.(Arg66Lys) View identifiers
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.

About CDK6

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.22×10⁻⁷ (1/1,606,862 alleles, no homozygotes), well below the PM2 threshold of <0.1%. It is also absent from gnomAD-Canada v1.0.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple in silico predictors support a benign impact. REVEL score is 0.192 (below deleterious threshold), BayesDel score is −0.083 (negative, predicting benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three independent in silico tools concur on a non-deleterious prediction.

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: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 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.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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. CDK6, an intracellular kinase, is amplified in various cancer types.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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 · 10 not met · 11 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001259.8:c.197G>A (p.Arg66Lys) is a missense variant in CDK6, a cyclin-dependent kinase with established oncogenic roles in cancer.

This variant is extremely rare, observed in only 1 of 1,606,862 alleles (AF=6.22×10⁻⁷) in gnomAD v4.1, and absent from gnomAD v2.1 and gnomAD-Canada v1.0, meeting PM2 at supporting level.

Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.192 (benign-leaning), BayesDel score is −0.083 (benign), and SpliceAI predicts no splicing impact (max delta=0.00), meeting BP4 at supporting benign level.

This variant is absent from ClinVar and has not been reported in the literature. No functional data, segregation data, de novo reports, or case-control studies are available.

The variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org, and no pathogenic missense variant at the same residue (Arg66) has been identified.

PVS1 is not applicable as this is a missense variant, not a null variant; BP1 is not applicable as CDK6 is an oncogene whose primary disease mechanism is gain-of-function rather than truncating loss-of-function.

Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. These criteria are in equipoise, resulting in a classification of Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 generic combination rules.

Met · 2

PM2 SupportingThis variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.22×10⁻⁷ (1/1,606,862 alleles, no homozygotes), well below the PM2 threshold of <0.1%. It is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: total AF=6.22e-7 (1/1
  • 606
  • 862 alleles
  • 0 homozygotes)
  • highest subpopulation AF=1.33e-5 in African/African American (1/74
  • 936)
  • gnomAD-Canada v1.0: absent.
Still missing
  • The single observed allele in gnomAD v4.1 is from the African/African American subpopulation
  • additional population data from underrepresented groups would strengthen the assessment.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple in silico predictors support a benign impact. REVEL score is 0.192 (below deleterious threshold), BayesDel score is −0.083 (negative, predicting benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three independent in silico tools concur on a non-deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL=0.192 (threshold >0.5 for pathogenic)
  • BayesDel=−0.083 (negative score favors benign)
  • SpliceAI max delta=0.00 (no splice effect).
Sources
revelbayesdelspliceai ↗

Not met · 10 · evaluated, threshold not reached

PS1 No alternative nucleotide change at position c.197 producing the same amino acid change (p.Arg66Lys) has been reported as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for this variant or for any alternative nucleotide change at codon 66 producing p.Arg66Lys.
Still missing
  • No prior reports of any variant at this codon.
Sources
clinvar ↗
PS3 No functional studies have been identified for this variant or for a systematically characterized range that includes codon 66 of CDK6. Details ▾Hide ▴
Evidence considered
  • OncoKB assigns Unknown Oncogenic Effect with no variant-specific functional evidence. Literature screening identified zero PMIDs with variant-specific data.
Still missing
  • No experimental functional characterization of p.Arg66Lys or a saturated mutagenesis range covering this residue.
Sources
oncokb ↗
PM1 Residue 66 does not lie within a statistically significant mutational hotspot as determined by cancerhotspots.org, and no domain-level functional characterization specific to this region of CDK6 was identified in the literature. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org reports this residue is not in a statistically significant hotspot. No curated domain-specific functional literature was retrieved.
Still missing
  • Absence of domain-specific functional characterization of the N-terminal kinase lobe region surrounding Arg66.
Sources
oncokb ↗
PM5 No pathogenic missense variant at the same amino acid residue (Arg66) has been identified. Automated PM5 candidate harvesting returned no comparator variants. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found zero same-residue comparator variants in ClinVar.
Still missing
  • No alternative missense change at codon 66 has been reported in ClinVar.
Sources
pm5_candidatesclinvar ↗
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.192 (below the pathogenic threshold of 0.5), BayesDel score is −0.083 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL=0.192 (benign-leaning)
  • BayesDel=−0.083 (benign)
  • SpliceAI max delta=0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
PP5 This variant has not been reported as pathogenic by a reputable source in the recent literature or clinical databases. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar. Literature screening identified no PMIDs with variant-specific data.
Still missing
  • No prior report of this variant in any clinical or research context.
Sources
clinvar ↗
BA1 The allele frequency is 6.22×10⁻⁷ (0.000062%) in gnomAD v4.1, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF=6.22e-7
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 The allele frequency is 6.22×10⁻⁷ (0.000062%) in gnomAD v4.1, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF=6.22e-7
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS2 No homozygous observations have been reported in population databases; the variant is present in heterozygous state in only 1/1,606,862 alleles in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
  • Zero homozygotes observed in gnomAD v2.1
  • v4.1
  • or gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PS5 This variant has not been reported as pathogenic by any reputable source. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar and has not been reported as pathogenic by any submitter or expert panel.
Still missing
  • No prior classification by any clinical laboratory or expert panel.
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
  • No parental testing or trio data available.
PS4 No case-control or prevalence data are available for this variant. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no affected vs. control cohort data identified.
Still missing
  • No cohort or case-control studies include this variant.
Sources
clinvar ↗
PM6 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing or trio sequencing data available.
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or cosegregation analysis available.
PP2 Gene-specific constraint data are not available; the HCI prior does not support CDK6. Missense constraint (Z-score) and benign missense rate cannot be evaluated for this gene with current data. Details ▾Hide ▴
Evidence considered
  • HCI prior probability is not available for CDK6 (gene not supported).
Still missing
  • No gene-specific missense constraint metric (e.g.
  • gnomAD missense Z-score) retrieved.
PP4 No patient-specific phenotype or clinical data are available for assessment. Details ▾Hide ▴
Still missing
  • No proband phenotype or clinical history provided.
BS3 No in vitro or in vivo functional studies demonstrating a benign effect are available for this variant. Details ▾Hide ▴
Still missing
  • No experimental functional data exist for this variant.
BS4 No family segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family studies available.
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
  • No phase or trans configuration data available.
BP5 No data are available regarding an alternative molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
  • No proband-level data to evaluate an alternative cause.
BP6 This variant has not been reported as benign by any reputable source. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no benign classification exists.
Still missing
  • No prior clinical classification of any kind.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Arg66Lys); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The variant does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a null variant
  • PVS1 is structurally inapplicable.
Sources
pvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders with a pathogenic variant in trans; no recessive inheritance pattern or trans configuration data are available for this variant, and CDK6 is not associated with a recessive disorder. Details ▾Hide ▴
Evidence considered
  • Variant not assessed in a recessive disease context
  • no trans data.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants; this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant is a substitution
  • not an in-frame indel or stop-loss.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. CDK6 is a proto-oncogene whose primary pathogenic mechanism in cancer is gain-of-function (amplification or activating missense), not loss-of-function truncation. Germline CDK6 loss-of-function is not an established primary disease mechanism for a Mendelian disorder. Details ▾Hide ▴
Evidence considered
  • CDK6 is characterized as an oncogene amplified in cancer
  • truncating variants are not the established primary germline disease mechanism.
Sources
oncokb ↗
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
  • Variant is a substitution
  • not an in-frame indel in a repetitive region.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (c.197G>A, p.Arg66Lys) and therefore does not qualify. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Identifiers

Gene
CDK6
Transcript
NM_001259.8
Coding (HGVS c.)
NM_001259.8:c.197G>A
Protein (HGVS p.)
NP_001250.1:p.(Arg66Lys)
GRCh38
chr7:92833127 C>T
GRCh37
chr7:92462441 C>T

Gene diagram

Every interpreted variant in CDK6, mapped onto the exon structure of NM_001259.8. Select a row to find it on the plot.

CDK6NM_001259.8
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,606,862 alleles AF 6.22e-07 · 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 6.2e-07 · 1 / 1,606,862 alleles · 0 hom
African/African American1 / 74,936 1.3e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.22331e-07; MAF= 0.00006%, 1/1606862 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33447e-05; MAF= 0.00133%, 1/74936 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.192
BayesDel
-0.083

How the predictions were used

BP4 SupportingMultiple in silico predictors support a benign impact. REVEL score is 0.192 (below deleterious threshold), BayesDel score is −0.083 (negative, predicting benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three independent in silico tools concur on a non-deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL=0.192 (threshold >0.5 for pathogenic)
  • BayesDel=−0.083 (negative score favors benign)
  • SpliceAI max delta=0.00 (no splice effect).
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.192 (below the pathogenic threshold of 0.5), BayesDel score is −0.083 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL=0.192 (benign-leaning)
  • BayesDel=−0.083 (benign)
  • SpliceAI max delta=0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (c.197G>A, p.Arg66Lys) and therefore does not qualify. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.192. BayesDel score = -0.0828048.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,606,862 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 Captured ClinVar source record 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

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= 6.22331e-07; MAF= 0.00006%, 1/1606862 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33447e-05; MAF= 0.00133%, 1/74936 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.192. BayesDel score = -0.0828048.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK6, an intracellular kinase, is amplified in various cancer types.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.