NM_001259.8:c.334G>A

CDK6 · NP_001250.1:p.(Val112Ile) · NM_001259.8

GRCh37: chr7:92404045 C>T · GRCh38: chr7:92774731 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.(Val112Ile)

gnomAD AF

4.96923422858229e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001259.8:c.334G>A (p.Val112Ile) in CDK6 is a missense variant absent from ClinVar and observed at ultra-rare frequency in gnomAD (AF=4.97e-6 in v4.1, 2-8 total alleles across datasets).

PM2 (supporting) is met: the variant is present at extremely low frequency across gnomAD populations (highest subpopulation AF=6.70e-5), well below the 0.1% threshold.

BP4 (supporting benign) is met: multiple independent computational predictors — REVEL (0.114), BayesDel (-0.467), and SpliceAI (0.00) — concur that the variant is likely neutral with no predicted impact on splicing or protein function.

PVS1 is not applicable: this is a missense variant, not a null variant, and does not meet the ClinGen SVI PVS1 criteria (PMC6185798).

No functional data (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), case-control data (PS4), or ClinVar classifications (PS5/PP5/BP6) are available for this variant.

With PM2 (supporting pathogenic) and BP4 (supporting benign), the evidence is balanced and insufficient to classify beyond a Variant of Uncertain Significance per ACMG/AMP 2015 framework.

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	PVS1 is not applicable to this missense variant (NM_001259.8:c.334G>A; p.Val112Ile). The variant does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change at the same codon producing an identical amino acid change that has been established as pathogenic. No known pathogenic variant at codon 112 of CDK6 has been identified in ClinVar or the literature, and no alternative nucleotide change resulting in V112I has been reported as pathogenic.	clinvar pm5_candidates
PS2	Not met	PS2 requires a confirmed de novo observation with both parental samples tested. No de novo data is available for this variant.
PS3	Not met	PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No functional data exists for NM_001259.8:c.334G>A. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No publications mention this variant. In silico predictions alone (REVEL 0.114, BayesDel -0.467) are not a substitute for experimental functional evidence.	oncokb
PS4	Not met	PS4 requires a significantly increased prevalence of the variant in affected individuals compared to controls. No case-control data or cohort prevalence data is available for this variant.
PS5	Not met	PS5 requires a reputable source to have classified the variant as pathogenic. This variant is absent from ClinVar and has not been reported as pathogenic by any submitted source.	clinvar
PM1	Not met	PM1 requires the variant to be located in a mutational hotspot and/or critical and well-established functional domain without benign variation. Cancerhotspots.org does not identify residue 112 as a statistically significant hotspot. No literature was identified that characterizes position Val112 as a critical functional domain. Without domain-level evidence or a known hotspot, PM1 is not met.
PM2	Met	PM2 applies when a variant is absent from or observed at extremely low frequency in large population databases. This variant is present in gnomAD v2.1 at AF=7.20e-6 (2/277,844 alleles) and in gnomAD v4.1 at AF=4.97e-6 (8/1,609,906 alleles), with no homozygotes. The highest observed population frequency is 6.70e-5 (African/African American, gnomAD v4.1), well below the 0.1% threshold. Absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid position. No pathogenic or likely pathogenic comparator variants at codon 112 of CDK6 were identified in ClinVar or the literature.	pm5_candidates clinvar
PM6	Not met	PM6 requires a de novo observation without confirmation of paternity and maternity. No de novo data is available for this variant.
PP1	Not met	PP1 requires co-segregation with disease in multiple affected family members. No segregation data is available for this variant.
PP2	Not met	PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While CDK6 is implicated in cancer through somatic alterations, no germline disease mechanism with missense variants as the primary mechanism has been established. Gene-level constraint metrics are not available to support a low rate of benign missense variation.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.114 (below the 0.5 threshold typically used for deleterious prediction), BayesDel score is -0.467 (negative score predicts benign), and SpliceAI max delta is 0.00 (no predicted splice impact). All three in silico predictors favor a benign or neutral effect; no lines of computational evidence support pathogenicity.	revel bayesdel spliceai
PP4	Not met	PP4 requires the variant to be found in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology. No phenotype or family history data is available for this case.
PP5	Not met	PP5 requires a reputable source to have classified the variant as pathogenic. This variant is absent from ClinVar and has not been reported by any submitter. No 3-star expert panel classification exists for this variant.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in any general population. The highest observed population frequency is 6.70e-5 (0.0067%) in the African/African American population (gnomAD v4.1), which is well below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in any population. The highest observed population frequency is 6.70e-5 (0.0067%) in the African/African American population (gnomAD v4.1), which is well below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a homozygous state, in trans with a pathogenic variant, or in cis with a pathogenic variant in a healthy individual. No homozygotes are observed in gnomAD, and no data regarding trans or cis configuration with pathogenic variants is available.	gnomad_v2 gnomad_v4
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No experimental functional studies exist for this variant. In silico predictions (REVEL 0.114, BayesDel -0.467) suggest a benign effect but are not a substitute for well-established functional studies.
BS4	Not met	BS4 requires lack of segregation with disease in multiple affected family members. No segregation data is available for this variant.
BP1	Not met	BP1 applies to missense variants in genes where only truncating variants are known to cause disease. CDK6 is primarily associated with somatic alterations in cancer; the germline disease mechanism is not well-characterized with either a truncating-only or missense-inclusive pattern. This criterion does not apply in the absence of an established germline truncating-only disease mechanism.
BP2	Not met	BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No such data is available.
BP4	Met	BP4 applies when multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.114 (below the typical 0.5 deleterious threshold), BayesDel score is -0.467 (negative, predicting a benign/neutral effect), and SpliceAI max delta score is 0.00 (no predicted splice impact). Three independent computational predictors concur that this variant is likely benign.	revel bayesdel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data is available for this case.
BP6	Not met	BP6 requires a reputable source to have classified the variant as benign. This variant is absent from ClinVar and has not been classified by any submitter. No 3-star expert panel classification exists for this variant.	clinvar
BP7	N/A	BP7 applies only to synonymous variants with no predicted splice impact. NM_001259.8:c.334G>A is a missense variant (p.Val112Ile) and does not qualify for BP7 assessment.

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