NM_000075.3:c.322C>T

CDK4 · NP_000066.1:p.(Pro108Ser) · NM_000075.3

GRCh37: chr12:58145022 G>A · GRCh38: chr12:57751239 G>A

Gene: CDK4 Transcript: NM_000075.3

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

CDK4

Transcript

NM_000075.3

Protein

NP_000066.1:p.(Pro108Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000075.3:c.322C>T (p.Pro108Ser) is a missense variant in CDK4, a gene in which activating missense variants are associated with autosomal dominant familial melanoma.

This variant is absent from all large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting moderate evidence for pathogenicity (PM2).

Multiple lines of computational evidence suggest a benign effect: REVEL score is 0.251 (below the pathogenic threshold), BayesDel score is -0.25851 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta = 0.01). This supports BP4 (supporting benign).

No functional studies, case-control data, segregation data, or clinical phenotype information are available for this variant. The variant is absent from ClinVar and has not been reported in the somatic or germline literature.

The variant is a missense substitution at a residue (Pro108) that is not a recognized mutational hotspot and has no comparator pathogenic variants at the same position.

Overall, the only applicable criterion is PM2 (moderate) for absence from population databases, and BP4 (supporting benign) for concordant benign computational predictions. With one moderate pathogenic criterion and one supporting benign criterion, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic, and insufficient evidence exists to classify it as benign. This variant is classified as a 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	This is a missense variant (c.322C>T, p.Pro108Ser) and does not fall into the null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798): nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions.	pvs1_generic_framework
PS1	Not met	A different pathogenic missense change at the same amino acid residue (Pro108) has not been reported in ClinVar or the literature. There are no comparator variants at this position to satisfy PS1.	clinvar
PS2	Not met	No de novo occurrence with confirmed paternity and maternity has been reported for this variant in the literature or available case data.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for NM_000075.3:c.322C>T (p.Pro108Ser) or a systematically characterized range that includes this position. Computational predictions alone (REVEL 0.251, BayesDel -0.25851) do not constitute functional evidence.	oncokb revel bayesdel
PS4	Not met	No case-control studies or cohort analyses demonstrate enrichment of this variant in affected individuals compared to controls. The variant has not been reported in any clinical case series.
PS5	Not met	This variant is absent from ClinVar entirely; no reputable source has classified it as pathogenic. PS5 requires at least a database entry with pathogenic classification from a reputable source.	clinvar
PM1	Not met	This variant (p.Pro108Ser) does not lie within a statistically significant mutational hotspot as assessed by cancerhotspots.org, and no literature was identified characterizing residue Pro108 as part of a critical functional domain with established pathogenic missense variation. Residue PM1 requires a mutational hotspot or a well-characterized functional domain where missense variants are established as pathogenic.
PM2	Met	This variant is absent from all large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with a combined allele count of zero across all populations. Under generic ACMG/AMP rules, an allele frequency below 0.1% in population databases supports moderate evidence for pathogenicity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense variant has been reported at the same amino acid residue (Pro108) in CDK4. Automated PM5 candidate harvesting found zero same-residue comparator variants in ClinVar, and manual review confirmed no candidates.	clinvar
PM6	Not met	No de novo observation (without confirmation of paternity) has been reported for this variant in the literature or available case data.
PP1	Not met	No co-segregation data with disease in multiple affected family members is available for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation (typically Z-score > 3.09) where missense variants are a common disease mechanism. While CDK4 has known pathogenic activating missense variants in melanoma (e.g., R24C/H), constraint metrics establishing a low rate of benign missense variation were not available for this assessment.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.251 (below the 0.5 pathogenic threshold), BayesDel score is -0.25851 (negative, indicating benign), and SpliceAI predicts no splicing impact (max delta = 0.01). All available computational tools suggest a benign effect.	revel bayesdel spliceai
PP4	Not met	No phenotypic data or clinical history is available for the individual carrying this variant to assess phenotype specificity for a CDK4-associated disorder.
PP5	Not met	This variant is absent from ClinVar entirely; no reputable source has classified it as pathogenic. Under the applicable rules, a ClinVar entry with at least 3-star expert panel review would be required to apply PP5 at supporting strength, but no ClinVar entry exists for this variant.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the 1% threshold required for BA1 (stand-alone benign).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the 0.3% threshold required for BS1 (strong benign).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding the observation of this variant in healthy adult controls with full penetrance expected at an early age. BS2 requires observation in a healthy adult individual for a fully penetrant disorder.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. While in silico predictors are consistent with a benign effect (REVEL 0.251, BayesDel -0.25851, SpliceAI 0.01), computational predictions do not constitute the well-established functional evidence required for BS3.	revel bayesdel spliceai
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease in affected family members.
BP1	Not met	BP1 applies when a missense variant is found in a gene for which primarily truncating variants cause disease. CDK4-associated familial melanoma is caused by gain-of-function missense variants (e.g., p.Arg24Cys/His), not primarily by truncating loss-of-function variants. Therefore BP1 does not apply.
BP2	Not met	No data are available regarding observation of this variant in trans with a pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in a dominant disorder.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.251 (below the 0.5 pathogenic threshold and within the indeterminate-to-benign range), BayesDel score is -0.25851 (negative, indicating a benign prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). Three independent computational predictors are concordant in suggesting a benign effect.	revel bayesdel spliceai
BP5	Not met	No data are available demonstrating that this variant is found in a case with an alternate molecular basis for disease. BP5 requires identification of another pathogenic variant that explains the phenotype in the same individual.
BP6	Not met	This variant is absent from ClinVar entirely; no reputable source has classified it as benign. Under the applicable rules, a ClinVar entry with at least 3-star expert panel review would be required to apply BP6, but no ClinVar entry exists for this variant.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant (c.322C>T) is a missense substitution (p.Pro108Ser), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This is a single-nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders where a pathogenic variant is observed in trans. CDK4 is associated with autosomal dominant familial melanoma; recessive inheritance is not established.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide missense substitution.

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