NM_001238.4:c.254G>A

CCNE1 · NP_001229.1:p.(Arg85Gln) · NM_001238.4

GRCh37: chr19:30308117 G>A · GRCh38: chr19:29817210 G>A

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.(Arg85Gln)

gnomAD AF

4.02725647180115e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001238.4:c.254G>A (p.Arg85Gln) is a missense variant in CCNE1.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0064% (16/251,482 alleles), gnomAD v4.1 AF=0.0040% (65/1,614,002 alleles), with no homozygotes observed. The maximum subpopulation frequency is 0.051% in the South Asian population. These frequencies meet the PM2 threshold (<0.1%).

Multiple in silico prediction tools concordantly support a benign interpretation: REVEL score 0.031 (benign range), BayesDel score -0.586 (predicts benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These findings meet the BP4 threshold (multiple lines of computational evidence suggest no impact).

This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics; criteria provided, single submitter). No expert panel review or pathogenic assertion is available.

No variant-specific functional studies, de novo observations, segregation data, or case-control evidence are available.

Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): PM2 (supporting) is balanced by BP4 (supporting). Neither a pathogenic combination (requiring ≥2 supporting or ≥1 moderate + ≥1 supporting) nor a benign/likely benign combination (requiring ≥2 supporting benign or ≥1 strong benign + ≥1 supporting benign) is satisfied.

Overall classification: Uncertain significance.

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 reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_001238.4:c.254G>A is a missense variant (p.Arg85Gln) and does not fall into any PVS1 null-variant bucket per the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No established pathogenic variant causing the same amino acid change (p.Arg85Gln / R85Q) has been identified in ClinVar or the literature. The single ClinVar submission classifies this variant as Uncertain significance.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant. PS2 requires confirmation of both maternity and paternity in a de novo observation.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a deleterious effect of p.Arg85Gln have been identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically increased prevalence of this variant in affected individuals versus controls are available.
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 sequence variant interpretation framework (PMID:25741868). No VCEP-specific extension defines PS5 for this gene.
PM1	Not met	Residue 85 does not lie within a known mutational hotspot or a critical functional domain where pathogenic missense variants cluster and benign variation is absent. Systematic hotspot analysis found no statistically significant enrichment at this residue.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=6.36×10⁻⁵ (16/251,482 alleles), gnomAD v4.1 AF=4.03×10⁻⁵ (65/1,614,002 alleles), gnomAD-Canada AF=1.09×10⁻⁴ (2/18,412 alleles). Global allele frequency and grpmax FAF (0.000389) are well below the 0.1% PM2 threshold. No homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant has been established at the same residue (Arg85). Automated PM5 candidate harvesting was unable to identify any same-residue comparator variants with pathogenic classification.	pm5_candidates
PM6	Not met	No de novo observation of this variant has been reported. PM6 requires a de novo finding without confirmation of paternity and maternity.
PP1	Not met	No cosegregation data are available for this variant in affected families.
PP2	Not met	CCNE1 is not established as a gene in which missense variants are a common mechanism of disease with a low rate of benign missense variation. No gene-level missense constraint metric supports PP2 application.
PP3	Not met	Multiple in silico prediction tools support a benign interpretation: REVEL score 0.031 (strongly predicts benign; threshold >0.5 for pathogenic), BayesDel score -0.586 (negative, predicts benign), SpliceAI max delta 0.00 (no splicing impact). Computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype information is available to assess whether this variant occurs in a patient with a phenotype highly specific for CCNE1-related disease.
PP5	Not met	No reputable source has reported this variant as pathogenic. The single ClinVar submission classifies it as Uncertain significance (Ambry Genetics, criteria provided single submitter).	clinvar
BA1	Not met	Global allele frequency (gnomAD v4.1: 0.0040%; v2.1: 0.0064%) is far below the 1% BA1 threshold. Maximum subpopulation frequency (South Asian: 0.051%) also remains well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Global allele frequency (0.0040-0.0064%) and maximum subpopulation frequency (South Asian: 0.051%) are below the 0.3% BS1 threshold. The variant is not common enough in population databases to support a benign interpretation via BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No specific observation of this variant in a healthy adult individual for a fully penetrant disorder has been documented. While gnomAD includes generally healthy individuals, BS2 requires explicit evidence of the variant in a healthy individual with full penetrance expected at an early age.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of p.Arg85Gln have been identified. In silico predictions alone do not satisfy BS3.
BS4	Not met	No segregation data demonstrating lack of segregation with disease are available.
BP1	Not met	CCNE1 is not established as a gene in which only truncating (loss-of-function) variants cause disease. BP1 requires that the disease mechanism for the gene is exclusively through truncating variants, which has not been demonstrated for CCNE1.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in CCNE1 has been reported.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a single-nucleotide missense substitution.
BP4	Met	Multiple lines of computational evidence support a benign interpretation. REVEL score 0.031 is strongly in the benign range (threshold >0.5 for pathogenic), BayesDel score -0.586 is negative (predicts benign), and SpliceAI max delta score is 0.00 (no predicted splicing impact). These concordant predictions suggest the variant has no deleterious effect on the gene product.	revel bayesdel spliceai
BP5	Not met	No case has been identified in which this variant is found in a patient with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. The single ClinVar submission classifies it as Uncertain significance.	clinvar
BP7	N/A	BP7 is reserved for synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001238.4:c.254G>A is a missense variant (p.Arg85Gln), not synonymous.
PM3	N/A	PM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant. This is a single heterozygous missense substitution without phasing data for a gene without established recessive inheritance.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide missense substitution causing an amino acid change without altering protein length.

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