About CDK6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK6 c.763C>T, p.(His255Tyr)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases: absent from gnomAD v2.1 (exomes) and present at an allele frequency of 6.2 × 10⁻⁷ (1/1,614,060 alleles, 0 homozygotes) in gnomAD v4.1, well below the PM2 threshold of <0.1%. Also absent from gnomAD-Canada v1.0.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no deleterious effect: REVEL score 0.062 (benign, well below 0.5 pathogenicity threshold), BayesDel score -0.465931 (negative value, consistent with benign), and SpliceAI max delta 0.00 (no predicted splicing impact). Three independent in silico tools consistently support a benign interpretation.
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; 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,060 alleles
gnomAD v4.1: 1 / 1,614,060 alleles. Recorded AF 6.19556e-07. 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.
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
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 · 21 not met · 0 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_001259.8:c.763C>T (p.His255Tyr) is a missense variant in CDK6, a gene without an established ClinGen CSPEC/VCEP framework. Assessment follows generic ACMG/AMP 2015 guidelines (PMID:25741868).
This variant is extremely rare in population databases, present at an allele frequency of 6.2 × 10⁻⁷ (1/1,614,060 alleles, 0 homozygotes) in gnomAD v4.1 and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting level (PM2_Supporting).
Multiple in silico tools predict a benign effect: REVEL score 0.062, BayesDel score -0.465931, and SpliceAI max delta 0.00, meeting BP4 at supporting level (BP4_Supporting).
No pathogenic criteria above supporting level are met. PVS1 is not applicable (missense variant). PS1-PS5 are not met due to absence from ClinVar and lack of functional, segregation, or de novo data. PM1 and PM5 are not met. PP1-PP5 are not met.
No benign criteria above supporting level are met. BA1 and BS1 are not met (allele frequency far below thresholds). BS2-BS4 are not met. BP1, BP2, BP5, and BP6 are not met. BP3 and BP7 are not applicable.
With one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting), the evidence is balanced with no criteria above supporting strength on either side. Under ACMG/AMP 2015 combination rules, this results in a classification of Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases: absent from gnomAD v2.1 (exomes) and present at an allele frequency of 6.2 × 10⁻⁷ (1/1,614,060 alleles, 0 homozygotes) in gnomAD v4.1, well below the PM2 threshold of <0.1%. Also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles)
- gnomAD v4.1: 1 allele in 1
- 614
- 060 (AF = 6.2 × 10⁻⁷
- highest subpopulation AF = 8.5 × 10⁻⁷ in NFE
- 0 homozygotes)
- gnomAD-Canada v1.0: absent
Sources
BP4 SupportingMultiple lines of computational evidence predict no deleterious effect: REVEL score 0.062 (benign, well below 0.5 pathogenicity threshold), BayesDel score -0.465931 (negative value, consistent with benign), and SpliceAI max delta 0.00 (no predicted splicing impact). Three independent in silico tools consistently support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.062 (benign)
- BayesDel score: -0.465931 (benign)
- SpliceAI max delta: 0.00 (no splicing impact)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 This variant is absent from ClinVar. No prior classification exists for any nucleotide change at codon 255 resulting in the same amino acid substitution (p.His255Tyr). Insufficient evidence to apply PS1. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for NM_001259.8:c.763C>T or any other nucleotide change producing p.His255Tyr.
Still missing
- No ClinVar entry exists for this codon position to compare.
Sources
PS2 No de novo occurrence data with confirmed maternity and paternity is available for this variant. No publications report this variant in a de novo context. Details ▾Hide ▴
Still missing
- No de novo studies or case reports available.
PS3 No variant-specific functional studies were identified. OncoKB reports an Unknown Oncogenic Effect with no curated functional evidence for this variant. No publications mention NM_001259.8:c.763C>T. PS3 requires experimental evidence directly testing the variant or a systematically characterized range that includes codon 255; neither is available. Details ▾Hide ▴
Evidence considered
- OncoKB classification is 'Unknown Oncogenic Effect' with no variant-specific functional data. No PMIDs identified for functional studies.
Still missing
- No functional assays for CDK6 p.His255Tyr or a systematic characterization of the region including codon 255.
Sources
PS4 No case-control or prevalence data are available to assess whether this variant is significantly enriched in affected individuals versus controls. Details ▾Hide ▴
Still missing
- No cohort studies or case-control data identified.
PM1 Residue H255 is not located in a statistically significant mutational hotspot (cancerhotspots.org: residue_significant=false, exact_variant_listed=no). While H255 lies within the CDK6 protein kinase domain (approximately residues 13-300), the case dossier lacks specific evidence that pathogenic germline missense variants cluster at this position or that codon 255 is a critical functional site. Domain-level inference alone is insufficient without supporting evidence of variant enrichment or functional criticality at this specific residue. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org does not identify codon 255 as a significant hotspot. No published data supports clustering of pathogenic germline missense variants at this position.
Still missing
- No domain-specific mutational data for CDK6 kinase domain in germline disease context.
PM6 No de novo observation with confirmed maternity and paternity is available for this variant. Details ▾Hide ▴
Still missing
- No trio sequencing or de novo reports available.
PP1 No co-segregation data are available for this variant in affected families. Details ▾Hide ▴
Still missing
- No family studies or segregation data available.
PP2 Insufficient data to assess whether CDK6 has a low rate of benign missense variation. HCI prior score is not available for CDK6 (gene not supported in the HCI database). Without an HCI missense constraint metric, PP2 cannot be applied under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- HCI prior not available for CDK6 (gene_not_supported).
Still missing
- No missense constraint metric (e.g.
- Z-score
- HCI prior) available for CDK6.
PP3 In silico tools consistently predict a benign effect: REVEL score 0.062 (well below the 0.5 threshold), BayesDel score -0.465931 (negative value indicating benign), and SpliceAI shows no splicing impact (max delta 0.00). Multiple computational lines do not support a deleterious effect; PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.062 (benign
- below 0.5)
- BayesDel score: -0.465931 (benign
- negative value)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
PP4 No patient phenotype or clinical data are available for adjudication. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No proband phenotypic information provided.
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
BA1 Allele frequency of 6.2 × 10⁻⁷ (0.00006%) in gnomAD v4.1 is far below the BA1 threshold of >1%. This variant is not a common polymorphism. Details ▾Hide ▴
BS1 Allele frequency of 6.2 × 10⁻⁷ (0.00006%) in gnomAD v4.1 is far below the BS1 threshold of >0.3%. The variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴
BS2 No homozygous observations in population databases (gnomAD v4.1 homozygous count = 0; gnomAD v2.1 absent entirely). No evidence of healthy homozygous adult carriers. Details ▾Hide ▴
BS3 No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant. No publications mention NM_001259.8:c.763C>T, and OncoKB reports no functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional data. No PMIDs report functional studies for this variant.
Still missing
- No functional assays available for CDK6 p.His255Tyr.
Sources
BS4 No segregation data are available to assess whether this variant fails to segregate with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 CDK6 is not established as a gene where only truncating variants cause disease with missense variants being benign. The PVS1 gene-context literature search identified publications about CDK6's interaction with CDKN2A/CDKN2B, not primary CDK6 disease-causing germline mutations. CDK6 germline disease association remains undefined, and no evidence supports a truncating-only mechanism. Details ▾Hide ▴
Evidence considered
- PVS1 gene-context literature identifies CDK6 as interactor of CDKN2A/B
- not as a primary disease gene. No established truncating-only disease mechanism for CDK6.
Still missing
- CDK6 germline disease association is not well established.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No phase information available.
BP5 No case has been identified where this variant occurs in an individual with an alternate molecular basis for disease. No clinical phenotype data are available. Details ▾Hide ▴
Still missing
- No clinical phenotype or alternate molecular diagnosis data available.
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
PS5 No reputable source has classified this variant as pathogenic. The variant is entirely absent from ClinVar, and no published reports associate it with disease. Details ▾Hide ▴
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001259.8:c.763C>T is a missense variant (p.His255Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense substitutions per the ClinGen PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 255
- variant bucket 'other'
- apply_generic_pvs1_framework is false per pvs1_variant_assessment.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant. CDK6 germline inheritance pattern is not established as recessive, and no second variant data are available. Not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length-changing variants (stop-loss, in-frame deletions/insertions) in non-repeat regions. NM_001259.8:c.763C>T is a missense substitution that does not alter protein length. Not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AAutomated PM5 candidate harvesting could not confirm classic same-residue PM5 semantics. No pathogenic missense variants at codon 255 (His) were identified in ClinVar. Manual review confirms no comparator variants exist at this residue. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 candidates. No ClinVar entries for any variant at codon 255 of CDK6.
Still missing
- No same-residue comparator variants available.
Sources
pm5_candidatesclinvar ↗
BP3 N/ABP3 applies to in-frame deletions or insertions in a repetitive region without a known function. This is a single-nucleotide missense substitution with no repetitive-region context. Not applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001259.8:c.763C>T is a missense variant (p.His255Tyr), not a synonymous substitution. Not applicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CDK6
- Transcript
- NM_001259.8
- Coding (HGVS c.)
- NM_001259.8:c.763C>T
- Protein (HGVS p.)
- NP_001250.1:p.(His255Tyr)
- GRCh38
- chr7:92618143 G>A
- GRCh37
- chr7:92247457 G>A
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…
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 CDK6
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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
1 / 1,614,060 alleles
AF 6.2e-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 / 1,614,060 alleles · 0 hom
| European (non-Finnish)1 / 1,179,904 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19556e-07; MAF= 0.00006%, 1/1614060 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47527e-07; MAF= 0.00008%, 1/1179904 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
- 0.062
- BayesDel
- -0.466
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no deleterious effect: REVEL score 0.062 (benign, well below 0.5 pathogenicity threshold), BayesDel score -0.465931 (negative value, consistent with benign), and SpliceAI max delta 0.00 (no predicted splicing impact). Three independent in silico tools consistently support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.062 (benign)
- BayesDel score: -0.465931 (benign)
- SpliceAI max delta: 0.00 (no splicing impact)
Sources
PP3 In silico tools consistently predict a benign effect: REVEL score 0.062 (well below the 0.5 threshold), BayesDel score -0.465931 (negative value indicating benign), and SpliceAI shows no splicing impact (max delta 0.00). Multiple computational lines do not support a deleterious effect; PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.062 (benign
- below 0.5)
- BayesDel score: -0.465931 (benign
- negative value)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001259.8:c.763C>T is a missense variant (p.His255Tyr), not a synonymous substitution. Not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.062. BayesDel score = -0.465931.
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 / 1,614,060 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001259.8%3Ac.763C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-92247457-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-92618143-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-92618143-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001259.8%3Ac.763C…
- OncoKB ↗www.oncokb.org/gene/CDK6/H255Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDK6+c.763C%3ET
- 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= 6.19556e-07; MAF= 0.00006%, 1/1614060 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47527e-07; MAF= 0.00008%, 1/1179904 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 = 0.062. BayesDel score = -0.465931.
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.