NM_053056.3:c.517_519delGAG

CCND1 · NP_444284.1:p.(Glu173del) · NM_053056.3

GRCh37: chr11:69458697 CGGA>C · GRCh38: chr11:69643929 CGGA>C

Gene: CCND1 Transcript: NM_053056.3

Final call

VUS

PM2 moderate PM4 moderate

Variant details

Gene

CCND1

Transcript

NM_053056.3

Protein

NP_444284.1:p.(Glu173del)

gnomAD AF

6.817097279978185e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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	In-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.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No 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.	clinvar
PS2	N/A	No de novo observation data available for this variant. PS2 requires a confirmed de novo occurrence with maternity and paternity confirmed.
PS3	N/A	No 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.	oncokb
PS4	N/A	No case-control or cohort data available to assess enrichment of this variant in affected individuals versus controls.
PS5	N/A	No 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.	clinvar
PM1	Not met	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.
PM2	Met	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 gnomad_v4 gnomad_canada
PM4	Met	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.	pvs1_variant_assessment
PM5	N/A	PM5 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.	pm5_candidates
PM6	N/A	No 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.
PP1	N/A	No segregation data available. PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	N/A	No 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.
PP5	N/A	This 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.	clinvar
BA1	Not met	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).	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is far below the >0.3% BS1 threshold. All population-specific AFs are <0.0011%.	gnomad_v2 gnomad_v4
BS2	N/A	BS2 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.	gnomad_v2 gnomad_v4
BS3	N/A	No well-established functional studies demonstrate no deleterious effect for this variant. OncoKB reports Unknown Oncogenic Effect with no functional data.	oncokb
BS4	N/A	No segregation data available to demonstrate lack of cosegregation with disease. BS4 requires observation of the variant in multiple unaffected family members discordant with disease.
BP1	N/A	BP1 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.
BP2	N/A	No 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.
BP3	N/A	BP3 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.
BP4	Not met	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.	spliceai
BP5	N/A	No 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.
BP6	N/A	No 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.	clinvar
BP7	N/A	BP7 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.

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.