NM_001259.8:c.197G>A

CDK6 · NP_001250.1:p.(Arg66Lys) · NM_001259.8

GRCh37: chr7:92462441 C>T · GRCh38: chr7:92833127 C>T

Gene: CDK6 Transcript: NM_001259.8

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CDK6

Transcript

NM_001259.8

Protein

NP_001250.1:p.(Arg66Lys)

gnomAD AF

6.223309780180252e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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).	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at position c.197 producing the same amino acid change (p.Arg66Lys) has been reported as pathogenic.	clinvar
PS2	Not assessed	No de novo data are available for this variant.
PS3	Not met	No functional studies have been identified for this variant or for a systematically characterized range that includes codon 66 of CDK6.	oncokb
PS4	Not assessed	No case-control or prevalence data are available for this variant.	clinvar
PS5	Not met	This variant has not been reported as pathogenic by any reputable source.	clinvar
PM1	Not met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Arg66) has been identified. Automated PM5 candidate harvesting returned no comparator variants.	pm5_candidates clinvar
PM6	Not assessed	No de novo data are available for this variant.
PP1	Not assessed	No segregation data are available for this variant.
PP2	Not assessed	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.
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotype or clinical data are available for assessment.
PP5	Not met	This variant has not been reported as pathogenic by a reputable source in the recent literature or clinical databases.	clinvar
BA1	Not met	The allele frequency is 6.22×10⁻⁷ (0.000062%) in gnomAD v4.1, far below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	The allele frequency is 6.22×10⁻⁷ (0.000062%) in gnomAD v4.1, far below the BS1 threshold of >0.3%.	gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	No in vitro or in vivo functional studies demonstrating a benign effect are available for this variant.
BS4	Not assessed	No family segregation data are available to assess lack of segregation with disease.
BP1	N/A	BP1 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.	oncokb
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternative molecular basis for disease in a case harboring this variant.
BP6	Not assessed	This variant has not been reported as benign by any reputable source.
BP7	N/A	BP7 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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a single-nucleotide substitution.
PM3	N/A	PM3 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.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants; this variant is a missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.