Variant classification summary

NM_001759.3:c.389C>A

CCND2 · NP_001750.1:p.(Ser130Tyr) · NM_001759.3

GRCh37: chr12:4385364 C>A · GRCh38: chr12:4276198 C>A

Gene: CCND2 Transcript: NM_001759.3

Final call

VUS

PM2 moderate

Variant details

Gene

CCND2

Transcript

NM_001759.3

Protein

NP_001750.1:p.(Ser130Tyr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001759.3:c.389C>A (p.Ser130Tyr) in CCND2 is absent from all population databases, meeting PM2 at moderate strength.

2

No other pathogenic or benign criteria were met. PVS1 is not applicable for this missense variant. All remaining criteria are either not met, not assessed due to absence of data, or not applicable to this variant type.

3

With a single moderate pathogenic criterion (PM2) and no supporting criteria, the variant does not reach likely pathogenic, likely benign, or benign thresholds per generic ACMG/AMP 2015 combination rules (PMID:25741868). The 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	Variant is a missense substitution (p.Ser130Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus); does not meet the generic PVS1 framework criteria per ClinGen SVI recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	No previously established pathogenic variant at amino acid position Ser130 has been reported in ClinVar or the literature; variant is entirely absent from ClinVar.	clinvar
PS2	Not assessed	No de novo data (with confirmed paternity and maternity) are available for this variant in ClinVar or the literature.
PS3	Not assessed	No variant-specific functional studies identified. OncoKB reports 'Unknown Oncogenic Effect' with no curated functional evidence for this variant. No PMIDs with functional data were found.	oncokb
PS4	Not assessed	No case-control or cohort data available. Variant is absent from ClinVar with zero submissions, precluding any prevalence comparison.	clinvar
PS5	N/A	PS5 is not part of the standard ACMG/AMP 2015 criteria framework (PMID:25741868).
PM1	Not met	Residue Ser130 is not located in a statistically significant mutational hotspot (Cancer Hotspots: not significant). No evidence that this position lies within a critical functional domain devoid of benign variation.
PM2	Met	Variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele count 0 across all datasets). Meets PM2 threshold of <0.1% for non-VCEP generic ACMG.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid residue (Ser130) was identified in ClinVar for comparison; PM5 candidate harvesting returned zero same-residue comparators.	clinvar pm5_candidates
PM6	Not assessed	No de novo observation data available for this variant in ClinVar or literature; PM6 cannot be assessed without a de novo report.
PP1	Not assessed	No co-segregation data available. No family studies involving this variant have been reported.
PP2	Not assessed	CCND2 is associated with MPPH syndrome where heterozygous missense variants are a known disease mechanism (GeneReviews, PMID:27854409). However, quantitative constraint metrics to establish a low rate of benign missense variation (HCI prior unavailable for CCND2; no missense Z-score) are absent, precluding confident application of PP2.
PP3	Not met	Conflicting in silico predictions: REVEL score 0.585 (borderline, just above 0.5 threshold), BayesDel score 0.118 (low, not supporting pathogenicity), SpliceAI max delta 0.00 (no splice effect). Multiple lines of computational evidence do not converge on a deleterious prediction.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data are available; variant is not reported in ClinVar with associated phenotype information.
PP5	N/A	No reputable source (ClinVar, expert panel, or peer-reviewed publication) has classified this variant as pathogenic. The variant is absent from ClinVar entirely.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0). Does not meet the BA1 threshold of >1% allele frequency (non-VCEP generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from all population databases (AF=0). Does not meet the BS1 threshold of >0.3% allele frequency (non-VCEP generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	N/A	Variant has not been observed in any individual in population databases or ClinVar; no observation in a healthy adult homozygous state is possible for an absent variant.
BS3	Not assessed	No functional studies assessing this variant are available. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not assessed	No family segregation data available; no reports of non-segregation with disease phenotype.
BP1	N/A	CCND2-associated MPPH syndrome is primarily caused by missense (gain-of-function) variants, not truncating variants. BP1 applies only when the gene's disease mechanism is primarily through truncating variants.
BP2	Not assessed	No phase data available. No observations of this variant in trans or cis with another pathogenic variant.
BP4	Not met	In silico predictions do not support a benign interpretation. REVEL score 0.585 is above the benign range (<0.25). Evidence does not provide multiple lines of benign computational support.	revel bayesdel spliceai
BP5	Not assessed	No data available regarding an alternate molecular basis for disease in any individual carrying this variant.
BP6	N/A	No reputable source (ClinVar, expert panel, or peer-reviewed publication) has reported this variant as benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	Variant is a missense change (c.389C>A, p.Ser130Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame deletion or insertion.
PM3	N/A	Recessive-disorder criterion; CCND2-associated MPPH syndrome is autosomal dominant.
PM4	N/A	Protein-length change criterion; variant is a missense substitution, not an in-frame indel or stop-loss.

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