NM_006219.2:c.3200A>T

PIK3CB · NP_006210.1:p.(Asp1067Val) · NM_006219.2

GRCh37: chr3:138374244 T>A · GRCh38: chr3:138655402 T>A

Gene: PIK3CB Transcript: NM_006219.2

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

PIK3CB

Transcript

NM_006219.2

Protein

NP_006210.1:p.(Asp1067Val)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006219.2:c.3200A>T (p.Asp1067Val) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0).

The variant is absent from ClinVar and has no germline classification from any submitter.

Asp1067 resides in the C-terminal kinase domain of PIK3Cβ and lies within a statistically significant mutational hotspot (cancerhotspots.org). PMID:25982275 reports that D1067V is the most recurrent missense mutation in the PIK3Cβ kinase domain, accounting for ~15% of kinase domain missense mutations, and that D1067 is highly conserved across species.

Functional studies in PMID:25982275 demonstrate that PIK3Cβ/D1067V is a gain-of-function activating mutation in somatic cancer models (enhanced AKT/S6 phosphorylation, increased cell growth in vitro, tumor formation in vivo, erlotinib resistance). This evidence was not applied toward PS3 because the demonstrated gain-of-function mechanism does not align with the reported germline loss-of-function disease mechanism.

REVEL score of 0.65 suggests possible pathogenicity, but BayesDel (0.313) is borderline and SpliceAI predicts no splicing impact (max delta = 0.00). In silico evidence does not provide multiple converging lines for PP3 or BP4.

The variant has been observed 16 times in somatic cancers (COSMIC COSV56683107) and is classified as Oncogenic by OncoKB, but these pertain to somatic context and are not directly applicable to germline classification.

Two moderate pathogenicity criteria are met: PM1 (kinase domain hotspot) and PM2 (absent from population databases). No benign criteria are met. Per generic ACMG/AMP 2015 combination rules, two moderate criteria in the absence of benign criteria yields a classification of Likely Pathogenic.

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	NM_006219.2:c.3200A>T is a missense variant (p.Asp1067Val) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The PVS1 variant assessment confirmed variant_bucket='other' and apply_generic_pvs1_framework=false.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No same-amino-acid pathogenic comparator variant was identified. ClinVar is absent for this variant entirely, and the PM5 candidate search found zero same-residue comparator variants. Without a different nucleotide change at Asp1067 classified as pathogenic, PS1 cannot be applied.	clinvar pm5_candidates
PS2	Not met	No de novo observation with confirmed maternity and paternity was identified for this variant in any data source.
PS3	Not met	PMID:25982275 provides well-established functional evidence that PIK3Cβ/D1067V is a gain-of-function activating mutation (enhanced PI3K pathway signaling, increased cell growth in vitro, tumor formation in vivo, erlotinib resistance). However, this evidence is exclusively in a somatic cancer context demonstrating oncogenic activation. The germline disease mechanism reported for PIK3CB is loss of function, with which gain-of-function functional data do not align. Functional evidence from a somatic oncogenic context does not support a damaging effect consistent with the germline loss-of-function disease mechanism.	PMID:25982275
PS4	Not met	No case-control data comparing affected individuals to controls is available for this variant.
PS5	Not met	No reputable source has reported this variant as pathogenic in a germline context. OncoKB classifies it as Oncogenic in a somatic cancer context, which does not constitute a germline pathogenic assertion.	clinvar oncokb
PM1	Met	Asp1067 is located in the C-terminal kinase domain of PIK3Cβ, a critical functional domain. The residue lies in a statistically significant hotspot (cancerhotspots.org). PMID:25982275 demonstrates that D1067V is the most recurrent missense mutation in the PIK3Cβ kinase domain, accounting for ~15% of missense mutations in this domain. Multiple sequence alignment confirms D1067 is highly conserved across species.	PMID:25982275
PM2	Met	NM_006219.2:c.3200A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). The variant has an allele frequency of 0.0 in all population databases, which is well below the PM2 threshold of <0.1% for non-VCEP generic ACMG assessment.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator missense variants were identified in ClinVar. The PM5 candidate search found zero candidates with a different amino acid change at Asp1067. Without a confirmed pathogenic comparator at the same residue, PM5 cannot be assessed.	pm5_candidates clinvar
PM6	Not met	No de novo observation (with or without confirmed parentage) was identified for this variant.
PP1	Not met	No co-segregation data in affected family members is available for this variant.
PP2	Not met	No HCI prior probability score is available for PIK3CB (gene not supported in HCI database). Without an established low rate of benign missense variation and evidence that missense variants are a common disease mechanism, PP2 cannot be applied.
PP3	Not met	In silico evidence is mixed and does not provide multiple converging lines supporting a deleterious effect. REVEL score is 0.65 (above the 0.5 threshold), but BayesDel is 0.313 (borderline, just above ~0.27 threshold), and SpliceAI predicts no splicing impact (max delta = 0.00). Only one predictor (REVEL) clearly supports pathogenicity; this does not constitute multiple lines of computational evidence.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history information is available to assess specificity for a PIK3CB-related disease.
PP5	Not met	No reputable source has reported this variant as pathogenic in a germline context. OncoKB classification of Oncogenic pertains to somatic cancer, not germline disease.	clinvar oncokb
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.0, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.0, far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adults for a disorder with expected full penetrance at an early age.
BS3	Not met	Functional evidence from PMID:25982275 demonstrates a gain-of-function activating effect (enhanced PI3K signaling, increased cell growth, tumor formation), not a benign or neutral effect on protein function. This does not support a benign interpretation.	PMID:25982275
BS4	Not met	No segregation data in affected family members are available to assess lack of segregation.
BP1	Not met	While the PVS1 gene context reports loss-of-function as a supported disease mechanism, the evidence that primarily truncating variants (rather than missense) cause PIK3CB-related disease is not firmly established. The supporting germline disease papers are tangentially related (FMRP/fragile X, PTEN/autism, testicular cancer, addiction) and do not specifically establish a PIK3CB truncating-variant disease spectrum. BP1 cannot be applied without clear evidence that truncating variants are the primary cause of disease.	pvs1_gene_context
BP2	Not met	No data are available regarding observation of this variant in trans with a pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution.
BP4	Not met	In silico evidence does not support a benign interpretation. REVEL score of 0.65 suggests pathogenicity. BayesDel of 0.313 is borderline but does not clearly indicate benign effect. Multiple lines do not converge on a benign prediction.	revel bayesdel spliceai
BP5	Not met	No data are available identifying this variant in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. NM_006219.2:c.3200A>T is a missense variant (p.Asp1067Val), not a synonymous variant.

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