NM_053056.3:c.517_519del (p.Glu173del) is an in-frame deletion of a single amino acid in exon 3 of CCND1. This variant is extremely rare in population databases (gnomAD v2.1: 1/250,946 alleles, AF = 0.00040%; gnomAD v4.1: 11/1,613,590 alleles, AF = 0.00068%), meeting PM2 at moderate strength.1 As an in-frame deletion in a non-repeat region, the variant meets PM4 at moderate strength. The deletion removes Glu173, which lies within the cyclin C-terminal domain of CCND1.2 CCND1 has no established germline disease association and no CSPEC/VCEP framework exists for this gene. The pvs1_gene_context literature review claimed CCND1 loss-of-function as a germline mechanism, but the supporting papers do not actually study CCND1 germline disease: PMID:41429883 concerns PEG10/Silver-Russell syndrome, PMID:42295563 concerns DSP cardiomyopathy, PMID:30352907 concerns somatic urothelial carcinoma, PMID:30573562 concerns MYCN, and PMID:32737004 concerns colorectal cancer therapy. None of these papers discuss CCND1 germline loss-of-function variants.3 Two moderate pathogenic criteria are met (PM2, PM4), with zero benign criteria. Under generic ACMG/AMP 2015 combination rules, this is insufficient for a Likely Pathogenic classification (which requires at least 2 moderate + 1 supporting, or 1 pathogenic + ≥2 pathogenic criteria). The variant is classified as a Variant of Uncertain Significance (VUS).4
CCND1
Final classification
VUS
PM2PM4
CCND1
c.517_519del
p.Glu173del
This variant
NM_053056.3:c.517_519del (p.Glu173del) is an in-frame deletion of a single amino acid in exon 3 of CCND1. This variant is extremely rare in population databases (gnomAD v2.1: 1/250,946 alleles, AF = 0.00040%; gnomAD v4.1: 11/1,613,590 alleles, AF = 0.00068%), meeting PM2 at moderate strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, PM4 moderate; combination = 2 moderate, which maps to VUS.
Classification rationale
PM2PM4
VUS
CCND1 c.517_519del
PM2 + PM4
→
VUS
2
pvs1_variant_assessment
3
pvs1_gene_context
4
generic_acmg_combination_rules
Gene diagram
· NM_053056.3 · variants mapped to exon structure
CCND1
NM_053056.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 5 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
moderate
review
Pathogenic
This variant is extremely rare in population databases, with allele frequencies well below the 0.1% PM2 threshold. gnomAD v2.1: 1/250,946 alleles (AF = 3.98e-06, 0.00040%). gnomAD v4.1: 11/1,613,590 alleles (AF = 6.82e-06, 0.00068%; grpmax FAF = 4.29e-06). gnomAD-Canada: absent. No homozygotes observed in any database.
gnomAD v2.1: 1/250946 exomes (AF = 4.0e-06)highest in NFE (AF = 8.8e-06)
✓
PM4
moderate
review
Pathogenic
In-frame deletion of a single amino acid (p.Glu173del) in exon 3 of CCND1, in a non-repeat region. PM4 applies to protein length changes from in-frame deletions/insertions in nonrepeat regions. The deletion removes Glu173 within the cyclin C-terminal domain but does not lie in the C-terminal poly-glutamic acid repetitive tract.
In-frame deletion: NM_053056.3:c.517_519del removes one codon (GAG)resulting in p.Glu173delDeletion is in exon 3 (of 5)
Assessed · not applied
· 5 not met · 0 not assessed
Pathogenic
PM1
The variant does not lie in a statistically significant mutational hotspot.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
Benign
BA1
Allele frequency is far below the >1% BA1 threshold.
BS1
Allele frequency is far below the >0.3% BS1 threshold.
BP4
Multiple lines of computational evidence do not support a benign impact.
N/A · 20
PVS1 · PS1 · PS2 · PS3 · PS4 · PM5 · PM6 · PP1 · PP2 · PP4 · PP5 · BS2 · BS3 · BS4 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.8171e-06; MAF= 0.00068%, 11/1613590 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09782e-05; MAF= 0.00110%, 1/91090 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98492e-06; MAF= 0.00040%, 1/250946 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82068e-06; MAF= 0.00088%, 1/113370 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00068%
· 11 / 1,613,590
0 hom · FAF 0.00043%
0 hom · FAF 0.00043%
South Asian 1 / 91,090 |
0.0011% |
European (non-Finnish) 10 / 1,180,006 |
0.00085% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 250,946
0 hom
0 hom
European (non-Finnish) 1 / 113,370 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
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.
Sources & reference links