About CCND1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CCND1 c.517_519del, p.(Glu173del)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Moderate
PM2 · moderate
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.
PM4Moderate
PM4 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
11 / 1,613,590 alleles
gnomAD v4.1: 11 / 1,613,590 alleles. Recorded AF 6.8171e-06. Recorded homozygote count 0.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 0 not assessed · 21 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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).
No criteria match.
Met · 2
PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/250
- 946 exomes (AF = 4.0e-06)
- highest in NFE (AF = 8.8e-06)
- gnomAD v4.1: 11/1
- 613
- 590 (AF = 6.8e-06)
- highest in SAS (AF = 1.1e-05)
- grpmax FAF = 4.3e-06
- gnomAD-Canada: absent
- All population AFs <0.1% PM2 threshold
- no homozygotes
Still missing
- CCND1 has no established germline disease association
- PM2 weight may be reduced in genes without confirmed disease mechanism
Sources
PM4 ModerateIn-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. Details ▾Hide ▴
Evidence considered
- In-frame deletion: NM_053056.3:c.517_519del removes one codon (GAG)
- resulting in p.Glu173del
- Deletion is in exon 3 (of 5)
- within the cyclin C-terminal domain
- Not in a known repetitive region (CCND1 poly-E repeat is C-terminal
- residues ~230-240)
Still missing
- No functional data to confirm whether deletion of Glu173 disrupts cyclin D1 function or CDK4/6 interaction
- CCND1 has no established germline disease association
- the clinical significance of an inframe deletion is uncertain
Sources
pvs1_variant_assessment
Not met · 5 · evaluated, threshold not reached
PM1 The variant does not lie in a statistically significant mutational hotspot. Cancer Hotspots analysis reports the E173 residue is not within a significant hotspot. PM1 requires location in a mutational hot spot or critical well-established functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue E173 not significant
- exact variant not listed
- No established CCND1 germline mutational hotspot exists
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel could not be computed for this inframe deletion variant. HCI prior is not available for CCND1. No in silico tools predict a damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score = 0.00 (no predicted splice impact)
- REVEL: not applicable (variant is not an SNV)
- BayesDel: not applicable (variant is not an SNV)
- HCI prior: gene not supported (CCND1)
Sources
BA1 Allele frequency is far below the >1% BA1 threshold. The highest population AF is 1.10e-05 (0.0011%) in South Asian (gnomAD v4.1). Details ▾Hide ▴
Evidence considered
- Max population AF: 1.10e-05 (gnomAD v4.1
- South Asian) — far below 1% BA1 threshold
- gnomAD v2.1 max AF: 8.82e-06 (NFE)
Sources
BS1 Allele frequency is far below the >0.3% BS1 threshold. All population-specific AFs are <0.0011%. Details ▾Hide ▴
Evidence considered
- Max population AF: 1.10e-05 (0.0011%) — far below 0.3% BS1 threshold
- gnomAD v4.1 grpmax FAF: 4.29e-06
Sources
BP4 Multiple lines of computational evidence do not support a benign impact. SpliceAI predicts no splice effect (max delta = 0.00), but REVEL and BayesDel could not be computed for this inframe deletion. A single neutral prediction from SpliceAI alone is insufficient to meet BP4's requirement for multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (neutral for splicing)
- REVEL: not applicable (not SNV)
- BayesDel: not applicable (not SNV)
- Insufficient multiple lines of evidence to meet BP4
Sources
Not applicable · 21· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIn-frame deletion of a single amino acid (p.Glu173del) does not fall into the null variant buckets defined by the ClinGen PVS1 framework (PMC6185798). Under generic PVS1 decision tree, this variant type ('other') is not eligible for default PVS1 application. The variant is not a nonsense, frameshift, or canonical ±1,2 splice consensus change. Details ▾Hide ▴
Evidence considered
- Variant class: inframe deletion (NM_053056.3:c.517_519del
- p.Glu173del)
- Variant bucket: 'other' — does not match PVS1 null-variant categories
- Automated PVS1 assessment: apply_generic_pvs1_framework = false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo previously classified pathogenic variant with the same amino acid change (p.Glu173del) exists in ClinVar or the literature. PS1 requires a known pathogenic variant at the same residue with the same amino acid alteration. Details ▾Hide ▴
Evidence considered
- ClinVar: absent
- no variation IDs
- no classifications
- no submissions
- Literature: no PMIDs with variant-specific evidence
Sources
PS2 N/ANo de novo observation data available for this variant. PS2 requires a confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or other evidence sources
PS3 N/ANo variant-specific functional evidence identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no supporting PMIDs. COSMIC reports no somatic occurrences. No published functional assays for NM_053056.3:c.517_519del (p.Glu173del) were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no PMIDs
- COSMIC: variant not reported in somatic cancers
- No functional assay publications identified
Sources
PS4 N/ANo case-control or cohort data available to assess enrichment of this variant in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
- No prevalence or case-control data available
PM5 N/APM5 requires a different missense change at the same residue that has been established as pathogenic. This variant is an inframe deletion, not a missense, and no same-residue comparator variants exist. Details ▾Hide ▴
Evidence considered
- Variant is an inframe deletion (p.Glu173del)
- not a missense
- PM5 candidate harvest: 0 candidates found
- eligible_for_classic_pm5_search = false
- No pathogenic missense variants at Glu173 identified
Sources
pm5_candidates
PM6 N/ANo de novo observation of this variant has been reported. PM6 requires a de novo occurrence with maternity and paternity unconfirmed. No such data exists for NM_053056.3:c.517_519del. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature
PP1 N/ANo segregation data available. PP1 requires cosegregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data available
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This variant is an inframe deletion, not a missense. Additionally, CCND1 has no established germline disease mechanism. Details ▾Hide ▴
Evidence considered
- Variant is an inframe deletion
- not a missense variant
- CCND1 has no established germline disease association
PP4 N/ANo patient phenotype data available to assess whether the variant carrier's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype data provided for variant carriers
PP5 N/AThis variant has not been reported as pathogenic by a reputable source. ClinVar has no entry for this variant; no diagnostic laboratory or expert panel has classified it. Details ▾Hide ▴
BS2 N/ABS2 requires observation of the variant in a healthy adult for a disorder with full penetrance expected early in life. CCND1 has no established germline disease with early-onset full penetrance, making this criterion inapplicable. While the variant is present in gnomAD (presumably healthy population cohorts), this cannot be interpreted under BS2 without a defined disease model. Details ▾Hide ▴
Evidence considered
- Variant observed in gnomAD (11 alleles in v4.1
- 1 in v2.1) which includes presumed healthy individuals
- No established CCND1 germline disease with defined penetrance or age of onset
Sources
BS3 N/ANo well-established functional studies demonstrate no deleterious effect for this variant. OncoKB reports Unknown Oncogenic Effect with no functional data. Details ▾Hide ▴
BS4 N/ANo segregation data available to demonstrate lack of cosegregation with disease. BS4 requires observation of the variant in multiple unaffected family members discordant with disease. Details ▾Hide ▴
Evidence considered
- No family segregation studies available
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is an inframe deletion, not a missense variant. CCND1 also has no established germline disease mechanism. Details ▾Hide ▴
Evidence considered
- Variant is an inframe deletion
- not a missense
- No established CCND1 disease mechanism
BP2 N/ANo data available on co-occurrence of this variant in trans with a pathogenic variant in a dominant disorder, or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No co-occurrence or phase data available
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. The p.Glu173del deletion is in exon 3 within the cyclin C-terminal domain, not in the CCND1 C-terminal poly-glutamic acid repetitive tract (residues ~230-240). It is not in a repetitive region. Details ▾Hide ▴
Evidence considered
- Deletion at Glu173 is in a non-repeat region (cyclin C-terminal domain)
- CCND1 poly-E repeat is C-terminal (residues ~230-240)
- E173 is not within this region
BP5 N/ANo observation of this variant in a case with an alternate molecular basis for disease. BP5 requires the variant to be found in an individual with an alternate, confirmed cause of their phenotype. Details ▾Hide ▴
Evidence considered
- No data on alternate molecular etiology in variant carriers
BP6 N/ANo reputable source has classified this variant as benign. ClinVar has no entry for NM_053056.3:c.517_519del. BP6 requires a recent benign classification from a reputable source. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no splice impact and the nucleotide is not highly conserved. This variant is an inframe deletion of three nucleotides (c.517_519del), not a synonymous substitution. Details ▾Hide ▴
Evidence considered
- Variant type: inframe deletion
- not a synonymous/silent variant
PS5 N/ANo alternative missense variant at the same residue (Glu173) has been established as pathogenic. ClinVar contains no CCND1 residue-specific pathogenic classifications, and no literature reports a pathogenic missense at E173. Details ▾Hide ▴
Evidence considered
- No alternative pathogenic variant at Glu173 identified in ClinVar or literature
Sources
Identifiers
- Gene
- CCND1
- Transcript
- NM_053056.3
- Coding (HGVS c.)
- NM_053056.3:c.517_519del
- Protein (HGVS p.)
- NP_444284.1:p.(Glu173del)
- GRCh38
- chr11:69643929 CGGA>C
- GRCh37
- chr11:69458697 CGGA>C
Gene diagram
Every interpreted variant in CCND1, mapped onto the exon structure of NM_053056.3. Select a row to find it on the plot.
CCND1NM_053056.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CCND1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
11 / 1,613,590 alleles
AF 6.82e-06 · 0 homozygotes · FAF 4.29e-06
gnomAD v2.1
1 / 250,946 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.8e-06 · 11 / 1,613,590 alleles · 0 hom · FAF 4.3e-06
| South Asian1 / 91,090 | 1.1e-05 |
| European (non-Finnish)10 / 1,180,006 | 8.5e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 250,946 alleles · 0 hom
| European (non-Finnish)1 / 113,370 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel could not be computed for this inframe deletion variant. HCI prior is not available for CCND1. No in silico tools predict a damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score = 0.00 (no predicted splice impact)
- REVEL: not applicable (variant is not an SNV)
- BayesDel: not applicable (variant is not an SNV)
- HCI prior: gene not supported (CCND1)
Sources
BP4 Multiple lines of computational evidence do not support a benign impact. SpliceAI predicts no splice effect (max delta = 0.00), but REVEL and BayesDel could not be computed for this inframe deletion. A single neutral prediction from SpliceAI alone is insufficient to meet BP4's requirement for multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (neutral for splicing)
- REVEL: not applicable (not SNV)
- BayesDel: not applicable (not SNV)
- Insufficient multiple lines of evidence to meet BP4
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no splice impact and the nucleotide is not highly conserved. This variant is an inframe deletion of three nucleotides (c.517_519del), not a synonymous substitution. Details ▾Hide ▴
Evidence considered
- Variant type: inframe deletion
- not a synonymous/silent variant
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,613,590 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_053056.3%3Ac.517_519delGAG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-69458697-CGGA-C?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-69643929-CGGA-C?dataset…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-69643929-CGGA-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_053056.3%3Ac.517_…
- OncoKB ↗www.oncokb.org/gene/CCND1/E173del
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CCND1+c.517_519del
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.