NM_053056.3:c.838G>T

CCND1 · NP_444284.1:p.(Glu280Ter) · NM_053056.3

GRCh37: chr11:69466000 G>T · GRCh38: chr11:69651232 G>T

Gene: CCND1 Transcript: NM_053056.3

Final call

VUS

PM2 supporting

Variant details

Gene

CCND1

Transcript

NM_053056.3

Protein

NP_444284.1:p.(Glu280Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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	This 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.	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	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.
PS3	Not met	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.	oncokb
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	Not met	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.	clinvar
PM1	Not met	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.
PM2	Met	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%.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.
PM6	Not met	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.
PP1	Not met	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.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not met	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.
PP5	Not met	No reputable source has definitively classified this variant as pathogenic. The variant is absent from ClinVar, and no diagnostic laboratory report is available.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.
BS4	Not met	No lack of cosegregation data are available. No studies have tracked this variant in families to demonstrate that it does not segregate with disease.
BP1	N/A	BP1 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.
BP2	Not met	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.
BP4	Not met	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.	spliceai bayesdel
BP5	Not met	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.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar, and no diagnostic laboratory has reported a benign interpretation.	clinvar
BP7	N/A	BP7 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.