Variant classification summary

NM_006218.4:c.2016-11G>A

PIK3CA · NP_006209.2:p.? · NM_006218.4

GRCh37: chr3:178938763 G>A · GRCh38: chr3:179220975 G>A

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.?

gnomAD AF

4.4913513021123265e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006218.4:c.2016-11G>A is an intronic variant in PIK3CA (intron 13, 11 bases upstream of exon 13). The variant has been observed at low frequency in population databases: 7/262,544 alleles in gnomAD v2.1 (AF 0.00267%) and 71/1,580,816 alleles in gnomAD v4.1 (AF 0.00449%), with no homozygotes.

2

SpliceAI predicts no splicing impact (max delta score = 0.00), suggesting the intronic nucleotide substitution does not create or disrupt a splice site.

3

This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (Labcorp Genetics, SCV002406335) with review status 'criteria provided, single submitter.' No expert panel classifications are available.

4

No functional studies, case reports, segregation data, or de novo observations have been published for this variant. All six associated ClinVar PMIDs are general practice guidelines or background reviews with no variant-specific evidence.

5

Under the Brain Malformations VCEP (v1.1.0) Tavtigian point framework, no pathogenic criteria are met and no benign criteria are met. The total point score is 0, which falls within the VUS range (0 to 5 points).

6

Multiple benign-suggesting criteria (BP4, BP7) could not be fully assessed due to missing computational data (varSEAK, MaxEntScan, PhyloP). If additional splicing prediction tools confirm no impact and PhyloP indicates low conservation, this variant may be reclassified toward likely benign.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 0, which maps to VUS under the specified Tavtigian-style ranges.

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	Not applicable per the Brain Malformations VCEP: the disease mechanism for PIK3CA is gain of function (GOF), and LOF/haploinsufficiency has not been clearly identified as a disease mechanism underlying brain malformations.	cspec
PS1	N/A	This intronic variant (c.2016-11G>A) does not produce an amino acid change; PS1 requires the same amino acid change as a previously established pathogenic variant.
PS2	Not met	No de novo observations have been reported for this variant. PS2 requires demonstration of the variant at detectable allele fraction in an affected tissue, absent from parental samples. No such evidence is available.
PS3	Not met	No well-established in vitro or in vivo functional studies have been performed for this variant. SpliceAI predicts no splicing impact (max delta = 0.00), but this alone does not constitute functional evidence of a damaging effect per VCEP PS3 requirements.	spliceai
PS4	Not met	No affected individuals with this variant have been reported in the literature or ClinVar with phenotype data suitable for VCEP Table 2A point assignment. PS4 requires PM2 first and case-level phenotype documentation; neither is satisfied.	clinvar
PS5	N/A	PS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the Brain Malformations VCEP specification.
PM1	N/A	This intronic variant (c.2016-11G>A) does not encode an amino acid residue and therefore cannot be mapped to the VCEP Table 4 critical functional domains (kinase domain AA 322-483 or AA 797-1068). PM1 assesses protein domain location.	cspec
PM2	Not met	This variant is present in gnomAD at frequencies exceeding the VCEP PM2 threshold of ≤1 individual. gnomAD v2.1: 7 alleles (AF 0.00267%); gnomAD v4.1: 71 alleles (AF 0.00449%). The variant is not absent or sufficiently rare to meet PM2_Supporting.	gnomad_v2 gnomad_v4
PM5	N/A	This intronic variant does not produce a missense change. PM5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been previously observed.
PM6	N/A	Not applicable per the Brain Malformations VCEP: this criterion is addressed under PS2 and is not used independently.	cspec
PP1	N/A	Not applicable per the Brain Malformations VCEP: disease-causing variants in these genes are germline mosaic, de novo, or mosaic, making co-segregation analysis inapplicable.	cspec
PP2	N/A	PP2 applies to missense variants in genes with low rates of benign missense variation. This is an intronic variant and does not qualify for missense constraint assessment.
PP3	N/A	Not applicable per the Brain Malformations VCEP: these variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss of function mechanisms.	cspec
PP4	N/A	Not applicable per the Brain Malformations VCEP: this criterion is accounted for under PS4.	cspec
PP5	N/A	Not applicable per the Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The allele frequency in gnomAD (0.0045% in v4.1) is well below the VCEP BA1 threshold of >0.0926%. The variant is too rare in population databases to apply the stand-alone benign criterion.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD (0.0045% in v4.1) is below the VCEP BS1 threshold of >0.0185%. The variant does not meet the strong benign population frequency criterion.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes are present in gnomAD (0 in both v2.1 and v4.1), and no well-phenotyped heterozygous family members have been reported. The VCEP requires ≥3 homozygotes or ≥3 heterozygous in well-phenotyped family members.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies have been performed demonstrating no damaging effect on protein function or splicing for this variant.
BS4	N/A	Not applicable per the Brain Malformations VCEP: these are de novo, germline mosaic, or post-zygotic mutations, making segregation analysis inapplicable.	cspec
BP1	N/A	Not applicable per the Brain Malformations VCEP: loss of function is not the disease mechanism for PIK3CA (gain of function).	cspec
BP2	Not met	No evidence is available indicating this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA.
BP4	Not assessed	This intronic variant is eligible for BP4 assessment per VCEP rules, and SpliceAI predicts no splicing impact (max delta = 0.00). However, the VCEP requires two out of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. Only SpliceAI data is available; varSEAK and MaxEntScan scores are absent. The criterion cannot be fully adjudicated without the remaining two tools.	spliceai
BP5	Not met	No evidence is available indicating this variant was found in a case with an alternate molecular basis for disease.
BP6	N/A	Not applicable per the Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Not met	This intronic variant is eligible for BP7 per VCEP rules, but no PhyloP conservation score is available to determine whether the nucleotide is non-conserved (PhyloP < 0.1 required). Without this data, the criterion cannot be met.

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