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CCND1c.838G>TUncertain significance
Print report
Variant interpretation report

CCND1 c.838G>T, p.(Glu280Ter)

NM_053056.3:c.838G>T NP_444284.1:p.(Glu280Ter) View identifiers
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.

About CCND1

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the generic ACMG PM2 threshold of allele frequency below 0.1%.

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 supporting; combination = 1 supporting, 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.

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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99919608, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 1 met · 20 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_053056.3:c.838G>T (NP_444284.1:p.Glu280Ter) is a nonsense variant in the last exon (exon 5/5) of CCND1, predicted to escape nonsense-mediated decay and produce a truncated protein lacking the terminal 10 amino acids.

The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 at supporting strength.

The variant is absent from ClinVar with no prior germline classifications available.

The variant has been reported somatically in COSMIC (COSV99919608, n=3) and is classified as Likely Oncogenic by OncoKB with a gain-of-function context, but no variant-specific functional studies or germline case reports are available.

SpliceAI predicts no splice impact (max delta score 0.00) and BayesDel score of 0.60222 provides borderline in silico evidence, insufficient to meet PP3 or BP4.

Four CCND1 functional domain papers were reviewed (PMID:16732330, PMID:17299095, PMID:9832503, PMID:9926916); none examined the specific variant p.Glu280Ter, and thus none provide criterion-level evidence for this variant.

PVS1 is not applicable because the nonsense variant in the last exon is predicted to escape NMD, and C-terminal truncations in CCND1 are associated with gain-of-function rather than loss-of-function. No other pathogenic or benign criteria were met, resulting in insufficient evidence for definitive classification under generic ACMG/AMP 2015 rules.

Met · 1

PM2 SupportingThe variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the generic ACMG PM2 threshold of allele frequency below 0.1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles across all populations)
  • Absent from gnomAD v4.1 (0 alleles across all populations)
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 20 · evaluated, threshold not reached

PS1 No nucleotide change at the same position has been previously established as pathogenic. This variant is absent from ClinVar and no published literature reports a pathogenic variant at c.838 in CCND1. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • No prior pathogenic classification at this nucleotide position
Sources
clinvar ↗
PS2 No de novo occurrence of NM_053056.3:c.838G>T has been reported in a patient with a CCND1-related phenotype, and no trio sequencing studies have identified this variant as de novo. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in exploratory literature search
Still missing
  • No trio sequencing data for CCND1 germline variants available
PS3 No well-established functional studies have been performed on the specific variant CCND1 p.Glu280Ter. Four CCND1 functional papers were reviewed (PMID:16732330, PMID:17299095, PMID:9832503, PMID:9926916) but none examined this exact variant. OncoKB curation suggests a gain-of-function mechanism for C-terminal CCND1 truncations but does not provide variant-specific functional evidence suitable for PS3. Details ▾Hide ▴
Evidence considered
  • OncoKB classifies variant as Likely Oncogenic with gain-of-function context
  • but this is a curated literature gateway
  • not primary functional evidence for the exact variant
Still missing
  • No variant-specific functional studies validating the biological effect of E280*
Sources
oncokb ↗167323301729909598325039926916
PS4 No case-control study comparing the frequency of c.838G>T in affected versus unaffected individuals is available. The variant is absent from gnomAD v2.1 and v4.1, precluding an odds ratio calculation. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD v2.1 and v4.1
  • No case-control or cohort studies available
Still missing
  • No cohort studies screening for CCND1 germline mutations in any cancer predisposition
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM1 The variant is not located within a statistically significant mutational hotspot per Cancer Hotspots analysis. Although residue E280 lies in the C-terminal regulatory domain of CCND1 near the T286 phosphorylation site, there is no established germline mutational hotspot at this region. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots residue-level analysis: not a statistically significant hotspot
  • No known pathogenic germline variants at or near codon 280
PM6 No assumed de novo occurrence of c.838G>T has been reported in the literature without confirmation of paternity and maternity. No publications describe this variant in a de novo context. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in exploratory literature search
Still missing
  • No observation of this variant as a presumed de novo event
PP1 No cosegregation data are available for c.838G>T with a CCND1-associated disease in multiple affected family members. No familial studies have reported this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data identified in exploratory literature search
Still missing
  • No familial CCND1 germline mutation studies available
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.00). BayesDel score is 0.60222, which is in a borderline range and does not provide strong evidence of pathogenicity. REVEL score is unavailable. As a nonsense variant in the last exon, PP3 is also not typically applied separately from PVS1 to avoid double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.00 (no predicted splice effect)
  • BayesDel score: 0.60222 (borderline
  • not strongly damaging)
  • REVEL: unavailable
Still missing
  • REVEL score unavailable for this variant
Sources
spliceai ↗bayesdel
PP4 No specific phenotype or family history data are available for the proband carrying this variant. PP4 requires a phenotype highly specific for the gene or disease, which cannot be assessed without clinical information. Details ▾Hide ▴
Evidence considered
  • No phenotypic data available for assessment
Still missing
  • No proband phenotype or family history data provided
PP5 No reputable source has definitively classified this variant as pathogenic. The variant is absent from ClinVar, and no diagnostic laboratory report is available. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, which does not meet the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency: 0% (absent) in both v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, which does not meet the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency: 0% (absent) in both v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No evidence that this variant has been observed in healthy adults at sufficient frequency to be considered benign. The variant is absent from gnomAD population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrate that CCND1 p.Glu280Ter has no damaging effect. The four CCND1 functional studies reviewed (PMID:16732330, PMID:17299095, PMID:9832503, PMID:9926916) do not examine this specific variant and cannot provide BS3 support. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional studies showing a benign effect
Still missing
  • No functional characterization of the E280* variant
Sources
167323301729909598325039926916
BS4 No lack of cosegregation data are available. No studies have tracked this variant in families to demonstrate that it does not segregate with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • No CCND1 variant segregation studies identified
BP2 No observation of CCND1 c.838G>T in trans with a known pathogenic variant in a different gene for a dominantly inherited disorder has been reported. CCND1 is not typically included on multi-gene panels for well-characterized dominant disorders. Details ▾Hide ▴
Evidence considered
  • No trans configuration data available
Still missing
  • CCND1 is not routinely tested in panels for established dominant disorders
BP4 Multiple lines of computational evidence do not provide a strong benign signal. SpliceAI predicts no splice impact (max delta 0.00), but BayesDel score of 0.60222 is in an intermediate range and does not independently support a benign interpretation. For a nonsense variant, BP4 is of limited applicability. Details ▾Hide ▴
Evidence considered
  • SpliceAI: no splice impact predicted (max delta 0.00)
  • BayesDel: 0.60222 (intermediate)
  • REVEL: unavailable
Still missing
  • No REVEL score available
Sources
spliceai ↗bayesdel
BP5 No case has been reported where this variant is found in a patient with an alternate molecular basis for disease. Insufficient clinical data are available to apply BP5. Details ▾Hide ▴
Evidence considered
  • No clinical data available for alternative molecular etiology
Still missing
  • No proband-level clinical or molecular data provided
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar, and no diagnostic laboratory has reported a benign interpretation. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
Sources
clinvar ↗
PS5 No reputable source has previously classified this variant as pathogenic. The variant is absent from ClinVar, and no diagnostic laboratory has reported it as causative. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar and other curated databases
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis nonsense variant (p.Glu280Ter) is in the last exon (exon 5/5) at codon 280 of 290 and is predicted to escape nonsense-mediated decay per PMC6185798. The truncated protein retains the cyclin box and CDK4-binding domain while losing only 10 C-terminal amino acids. CCND1 is an oncogene where C-terminal truncations that remove the T286 degron are associated with protein stabilization and gain-of-function rather than loss-of-function; therefore PVS1 is not applicable for this variant. Details ▾Hide ▴
Evidence considered
  • Nonsense variant in last exon (exon 5/5) at codon 280/290
  • predicted NMD escape
  • CCND1 C-terminal truncations are associated with protein stabilization and gain-of-function
Still missing
  • No direct experimental data confirming whether the E280* transcript escapes NMD in CCND1
  • No functional studies of the E280* truncated protein
Sources
pvs1_generic_framework ↗
PM5 N/APM5 is defined for novel missense variants at a residue where a different pathogenic missense change has been observed. NM_053056.3:c.838G>T is a nonsense variant, not a missense variant, so PM5 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_053056.3:c.838G>T is a nonsense (stop-gain) variant, not a missense variant, so PP2 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. NM_053056.3:c.838G>T is a nonsense variant, not a missense variant, so BP1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_053056.3:c.838G>T is a nonsense (stop-gain) variant, not a synonymous variant, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
CCND1
Transcript
NM_053056.3
Coding (HGVS c.)
NM_053056.3:c.838G>T
Protein (HGVS p.)
NP_444284.1:p.(Glu280Ter)
GRCh38
chr11:69651232 G>T
GRCh37
chr11:69466000 G>T
COSMIC
COSV99919608

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -93 bp
0.000
SpliceAI acceptor gainat -2 bp
0.000
SpliceAI donor lossat -422 bp
0.000
SpliceAI donor gainat -2 bp
0.000
Pangolin splice lossmagnitude shown
-0.070
Pangolin splice gain
0.280

Other predictors

REVEL
Not available
BayesDel
0.602

How the predictions were used

PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.00). BayesDel score is 0.60222, which is in a borderline range and does not provide strong evidence of pathogenicity. REVEL score is unavailable. As a nonsense variant in the last exon, PP3 is also not typically applied separately from PVS1 to avoid double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.00 (no predicted splice effect)
  • BayesDel score: 0.60222 (borderline
  • not strongly damaging)
  • REVEL: unavailable
Still missing
  • REVEL score unavailable for this variant
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence do not provide a strong benign signal. SpliceAI predicts no splice impact (max delta 0.00), but BayesDel score of 0.60222 is in an intermediate range and does not independently support a benign interpretation. For a nonsense variant, BP4 is of limited applicability. Details ▾Hide ▴
Evidence considered
  • SpliceAI: no splice impact predicted (max delta 0.00)
  • BayesDel: 0.60222 (intermediate)
  • REVEL: unavailable
Still missing
  • No REVEL score available
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_053056.3:c.838G>T is a nonsense (stop-gain) variant, not a synonymous variant, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.60222.

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1.
    No paper-specific finding is recorded.
    PMID 16732330 ↗
  • Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival.
    No paper-specific finding is recorded.
    PMID 17299095 ↗
  • Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
    No paper-specific finding is recorded.
    PMID 9832503 ↗
  • Functional domains in cyclin D1: pRb-kinase activity is not essential for transformation.
    No paper-specific finding is recorded.
    PMID 9926916 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.60222.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99919608, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.