NM_001238.4:c.617A>G

CCNE1 · NP_001229.1:p.(Tyr206Cys) · NM_001238.4

GRCh37: chr19:30312636 A>G · GRCh38: chr19:29821729 A>G

Gene: CCNE1 Transcript: NM_001238.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CCNE1

Transcript

NM_001238.4

Protein

NP_001229.1:p.(Tyr206Cys)

gnomAD AF

0.0003094422303797405 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): rare in gnomAD — highest observed allele frequency 0.05612%, below the 0.1% rarity threshold.

BP4 (Supporting): SpliceAI max delta 0.011, far below the ~0.2 splice-altering cutoff, indicating no splice impact.

Synthesis: two supporting criteria do not reach the strength required for a pathogenic or benign call under generic ACMG/AMP 2015 combination rules, so the variant is classified as VUS.

Final determination: Generic ACMG/AMP 2015 fallback: one supporting pathogenic criterion (PM2) plus one supporting benign criterion (BP4) does not reach any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold, so the variant is classified as 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	Not applicable: this missense substitution is not a null variant (no nonsense-mediated decay or truncation), so this criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing p.Tyr206Cys with an established pathogenic classification was found.	clinvar
PS2	Not assessed	Not assessed: no de novo observation, parental genotypes, or phenotype data were available.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay data (e.g., cyclin E1-CDK2 activity) for p.Tyr206Cys were identified in any source.
PS4	Not assessed	Not assessed: no case-control or cohort enrichment data for this variant were available.
PM1	Not met	Not met: residue 206 is not a significant hotspot per Cancerhotspots.org, and no evidence places it in a critical functional domain.	oncokb
PM2	Met	Met (supporting): highest observed allele frequency is 0.05612% (gnomAD v2.1 African/African American), below the 0.1% rarity threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband with this variant in trans with a pathogenic allele, or phase/segregation data, was documented.
PM4	N/A	Not applicable: this missense substitution causes no protein length change, so this insertion/deletion criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate missense change at codon 206 with an established pathogenic classification was found.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no de novo observation with confirmed parentage was documented.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree, relative genotypes, or informative meioses were provided.	generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no gene-specific evidence that missense variants cause disease; CCNE1 acts mainly through amplification and gain of function.	oncokb
PP3	Not met	Not met: REVEL score 0.465 lies in the indeterminate zone between the 0.290 benign and 0.644 pathogenic thresholds.	revel spliceai bayesdel
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-to-gene specificity evidence was available.
PP5	Not assessed	Not assessed: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: highest population allele frequency is 0.05612%, far below the 5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest ancestry-group allele frequency is 0.05612%, below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report zero homozygotes and no qualifying healthy-adult carrier data.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data showing normal activity for p.Tyr206Cys were identified.
BS4	Not assessed	Not assessed: no non-segregation observation (affected non-carrier or unaffected carrier) was provided.	generic_acmg_combination_rules
BP1	Not assessed	Not assessed: no gene-level mechanism data indicating CCNE1 disease is predominantly loss-of-function.
BP2	Not assessed	Not assessed: no observation of this variant in cis with a pathogenic allele or an alternative molecular diagnosis.
BP3	N/A	Not applicable: this missense substitution does not alter protein length in a repetitive region, so this criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.011, far below the ~0.2 splice-altering cutoff, indicating no splice impact.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no affected individual or independent molecular diagnosis was provided to establish an alternative cause.
BP6	Not assessed	Not assessed: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: this is a missense, not a synonymous variant, so the silent-variant premise does not apply.	generic_acmg_combination_rules

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