NM_001259.8:c.763C>T

CDK6 · NP_001250.1:p.(His255Tyr) · NM_001259.8

GRCh37: chr7:92247457 G>A · GRCh38: chr7:92618143 G>A

Gene: CDK6 Transcript: NM_001259.8

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CDK6

Transcript

NM_001259.8

Protein

NP_001250.1:p.(His255Tyr)

gnomAD AF

6.195556546844603e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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	NM_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).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	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.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or prevalence data are available to assess whether this variant is significantly enriched in affected individuals versus controls.
PS5	Not met	No reputable source has classified this variant as pathogenic. The variant is entirely absent from ClinVar, and no published reports associate it with disease.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Automated 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.	pm5_candidates clinvar
PM6	Not met	No de novo observation with confirmed maternity and paternity is available for this variant.
PP1	Not met	No co-segregation data are available for this variant in affected families.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	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.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar entirely.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not met	No homozygous observations in population databases (gnomAD v4.1 homozygous count = 0; gnomAD v2.1 absent entirely). No evidence of healthy homozygous adult carriers.	gnomad_v2 gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not met	No segregation data are available to assess whether this variant fails to segregate with disease in affected family members.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 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.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not met	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.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 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.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

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.