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CCND1
Final classification
VUS
CCND1 c.838G>T · p.Glu280Ter
CCND1

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.

Gene
CCND1
Transcript
NM_053056.3
HGVS · transcript:coding
NM_053056.3:c.838G>T
Consequence
N/A
GRCh38
chr11:69651232 G>T
GRCh37
chr11:69466000 G>T
Basis 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.
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.
Classification rationale
PM2 VUS
CCND1 c.838G>T

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.1 The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 at supporting strength.2 The variant is absent from ClinVar with no prior germline classifications available.3 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.4 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 BP4.5 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.

PM2 VUS
Gene diagram · NM_053056.3 · variants mapped to exon structure
CCND1 NM_053056.3
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      Population frequency
      Absent from gnomAD v4.1.
      Absent from gnomAD v2.1.
      This variant is absent from gnomAD-Canada.
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.60222.
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99919608, n = 3 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Literature · 4 PMIDs triaged · 4 high-priority
      4papers screened
      Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
      16732330 ↗ functional
      Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1.
      Although cyclin D1 is overexpressed in a significant number of human cancers, overexpression alone is insufficient to promote tumorigenesis. In vitro studies have revealed that inhibition of cyclin D1 nuclear export unmasks its neoplastic potential. Cyclin D1 nuclear export depends upon phosphorylation of a C-terminal residue, threonine 286, (Thr-286) which in turn promotes association with the nu
      BS3PM1PS3
      17299095 ↗ functional
      Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival.
      A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated 3'UTR
      BS3PM1PS3
      9832503 ↗ functional
      Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
      The activities of cyclin D-dependent kinases serve to integrate extracellular signaling during G1 phase with the cell-cycle engine that regulates DNA replication and mitosis. Induction of D-type cyclins and their assembly into holoenzyme complexes depend on mitogen stimulation. Conversely, the fact that D-type cyclins are labile proteins guarantees that the subunit pool shrinks rapidly when cells
      BS3PM1PS3
      9926916 ↗ functional
      Functional domains in cyclin D1: pRb-kinase activity is not essential for transformation.
      Although cyclin D1 plays a major role during cell cycle progression and is involved in human tumourigenesis, its domain structure is still poorly understood. In the present study, we have generated a series of cyclin D1 N- and C-terminal deletion constructs. These mutants were used to define the domains required for transformation of rat embryonal fibroblasts (REF) in cooperation with activated Ha
      BS3PM1PS3
      Sources & reference links
      7Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots