Classification rationale

PM2 BP4 VUS

CCND1 c.844G>A missense · exon 5

PM2 (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. BP4 (Supporting): REVEL 0.07 and SpliceAI max delta 0.001 predict no functional impact. PM2 and BP4 (both supporting), combined under the generic ACMG/AMP 2015 rules, do not meet any pathogenic or benign threshold, yielding a VUS classification.

PM2 + BP4 → VUS

Gene diagram · NM_053056.3 · variants mapped to exon structure

CCND1 NM_053056.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases.

gnomAD v2.1 reports the variant as absent.gnomAD v4.1 reports the variant as absent.gnomAD-Canada v1.0 reports the variant as absent.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): REVEL 0.07 is below the 0.29 benign-supporting threshold, indicating no predicted functional impact.

SpliceAI (source_registry 'spliceai') max delta score = 0.001 for NM_053056.3:c.844G>A across DS_AG/DS_AL/DS_DG/DS_DL, indicating no predicted splice disruption.REVEL score = 0.07 (source_registry 'revel'), below the ClinGen SVI-calibrated REVEL benign-supporting thresholds described in Pejaver et al. 2022 (PMID 36413997).BayesDel score -0.503138 was retrieved (source_registry 'bayesdel') but excluded from this determination because no verified, citable published calibration threshold for BayesDel is available to this pipeline.

spliceai ↗

Assessed · not applied · 3 not met · 19 not assessed

Pathogenic

PS1 Not assessed: no different nucleotide change producing the same p.Asp282Asn amino acid change has been established as pathogenic.

PS2 Not assessed: no de novo observation with parental testing was documented for this variant.

PS3 Not assessed: no published functional assay data (e.g., kinase or cell-cycle assays) were available for this variant.

PS4 Not assessed: no affected-case series, case-control comparison, or prevalence evidence was available.

PM1 Not assessed: no hotspot or functional-domain annotation exists for residue 282; cancerhotspots.org returned no entry.

PM3 Not assessed: no evidence places this variant in trans with a pathogenic variant for a recessive condition.

PM5 Not assessed: no different missense change at residue 282 has been established as pathogenic.

PM6 Not assessed: no suspected de novo occurrence without confirmed parentage was documented.

PP1 Not assessed: no family segregation data, informative meioses, or variant-positive relatives were documented.

PP2 Not assessed: no gene-level missense constraint or benign-variation rate data were available for CCND1.

PP3 Not met: REVEL 0.07 is far below the 0.644 pathogenic-supporting threshold, indicating no predicted damaging effect.

PP4 Not assessed: no patient phenotype or disease-specific clinical features were provided for evaluation.

PP5 Not assessed: the variant has no ClinVar record and no expert-panel pathogenic assertion.

Benign

BA1 Not met: the variant is absent from population databases, so no allele frequency reaches the stand-alone benign threshold.

BS1 Not met: the variant is absent from population datasets, so it does not exceed any expected benign frequency threshold.

BS2 Not assessed: no observations in healthy adults, incompatible phenotypes, or homozygous individuals were available.

BS3 Not assessed: no functional assay data, benign or damaging, were available for this variant.

BS4 Not assessed: no unaffected relative carrying the variant with adequate phenotype evaluation was documented.

BP1 Not assessed: no evidence establishes CCND1's disease mechanism as predominantly loss-of-function, which BP1 requires.

BP2 Not assessed: no phase information or co-occurrence with a pathogenic variant was documented.

BP5 Not assessed: no alternative molecular diagnosis evidence or patient phenotype was available to evaluate.

BP6 Not assessed: the variant has no ClinVar record and no expert-panel benign assertion.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.07. BayesDel score = -0.503138.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CCND1, a regulator of the cell cycle, is amplified in various cancer types including breast, head and neck, and bladder cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots