Variant classification summary

NM_006218.4:c.2937-15T>C

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

GRCh37: chr3:178951867 T>C · GRCh38: chr3:179234079 T>C

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.?

gnomAD AF

9.138509553208815e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006218.4:c.2937-15T>C is an intronic variant in PIK3CA located 15 bases upstream of exon 20.

2

PVS1 is not applicable per the ClinGen Brain Malformations VCEP v1.1.0: the disease mechanism for PIK3CA-related brain malformations is gain of function, not loss of function.

3

This variant is present in 17 individuals (0.00626% AF) in gnomAD v2.1 and 145 individuals (0.00914% AF) in gnomAD v4.1, exceeding the VCEP PM2 threshold of at most one individual.

4

No pathogenic criteria are met and most are not applicable due to the intronic nature of the variant or explicit VCEP exclusion. No benign criteria are met. The classification falls within the VUS range (0 to 5 points) under the Brain Malformations Tavtigian point framework.

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	PVS1 is not applicable per the ClinGen Brain Malformations VCEP v1.1.0: the disease mechanism for PIK3CA-related brain malformations is gain of function; loss of function and/or haploinsufficiency have not been identified as disease mechanisms.	cspec final_classification_framework
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. NM_006218.4:c.2937-15T>C is an intronic variant that does not alter an amino acid; PS1 cannot be applied to non-coding variants.
PS2	Not met	No de novo evidence is available for NM_006218.4:c.2937-15T>C. The VCEP requires either confirmed de novo with tissue mosaicism (PS2_Strong) or confirmed de novo without tissue data (PS2_Moderate). Neither criterion is satisfied by currently available evidence.
PS3	Not met	No well-established in vitro or in vivo functional studies are available for NM_006218.4:c.2937-15T>C. No functional data were identified in OncoKB, COSMIC, or the reviewed literature. The VCEP requires functional assays meeting SVI quality metrics (PMID:31892348); no qualifying studies exist for this variant.	cspec
PS4	Not met	No affected individuals with brain malformation phenotypes have been reported for NM_006218.4:c.2937-15T>C in the reviewed literature. The VCEP PS4 framework requires phenotypic case counting via Table 2A and is contingent on PM2 being met. Neither PM2 nor any case-level evidence is satisfied.	cspec
PS5	N/A	PS5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been established. NM_006218.4:c.2937-15T>C is an intronic variant that does not alter an amino acid; no amino acid residue is affected.
PM1	Not met	PM1_Supporting per the VCEP requires the variant to affect a residue within a critical functional domain listed in Table 4 (for PIK3CA: kinase domain AA 322-483 or kinase domain AA 797-1068). NM_006218.4:c.2937-15T>C is an intronic variant located 15 bases upstream of exon 20; it does not alter or reside within a coding amino acid and therefore does not affect a residue in an approved functional domain.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Not met	VCEP PM2_Supporting requires the variant to be absent or rare from controls with at most one individual (≤1) in an ethnically-matched cohort. NM_006218.4:c.2937-15T>C is observed in 17 individuals in gnomAD v2.1 and 145 individuals in gnomAD v4.1, far exceeding the one-person threshold.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	PM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been observed. NM_006218.4:c.2937-15T>C is an intronic variant with no amino acid consequence; the pm5_candidates pipeline confirms the variant class is not missense-like.	pm5_candidates
PM6	N/A	PM6 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is subsumed under PS2 and is not used independently.	cspec
PP1	N/A	PP1 is not applicable per the ClinGen Brain Malformations VCEP: disease-causing variants in PIK3CA-related brain malformations are germline mosaic, de novo, or mosaic; co-segregation analysis is not relevant.	cspec
PP2	N/A	PP2 is designed for missense variants in genes with low rates of benign missense variation (measured via missense constraint Z-score). NM_006218.4:c.2937-15T>C is an intronic variant and the PP2 missense constraint framework does not apply to non-coding variants.	cspec
PP3	N/A	PP3 is not applicable per the ClinGen Brain Malformations VCEP: traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms and are not designed for gain-of-function variants in PIK3CA.	cspec
PP4	N/A	PP4 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is accounted for under PS4.	cspec
PP5	N/A	PP5 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	VCEP BA1 requires an allele frequency above 0.0926%. NM_006218.4:c.2937-15T>C has a maximum observed population frequency of 0.01175% (Admixed American, gnomAD v2.1) and 0.01154% (European non-Finnish, gnomAD v4.1), both well below the BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	VCEP BS1 requires an allele frequency above 0.0185%. NM_006218.4:c.2937-15T>C has a maximum observed population frequency of 0.01175% (gnomAD v2.1 AMR), which is below the 0.0185% threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	VCEP BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous individuals in well-phenotyped family members. NM_006218.4:c.2937-15T>C has zero homozygotes in gnomAD v2.1 and v4.1, and no well-phenotyped family member data are available.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a neutral effect for NM_006218.4:c.2937-15T>C. The VCEP requires functional assays meeting SVI quality metrics (PMID:31892348); no qualifying benign functional studies exist for this variant.	cspec
BS4	N/A	BS4 is not applicable per the ClinGen Brain Malformations VCEP: disease-causing variants in PIK3CA-related brain malformations are de novo, germline mosaic, or post-zygotic mutations; segregation analysis is not applicable.	cspec
BP1	N/A	BP1 is not applicable per the ClinGen Brain Malformations VCEP: the disease mechanism for PIK3CA is gain of function; loss of function is not the disease mechanism, so the principle that primarily truncating variants cause disease does not apply.	cspec
BP2	Not met	BP2 requires observation of the variant in cis or trans with a known pathogenic variant in the same gene. No phasing data or co-occurrence with a known pathogenic PIK3CA variant has been reported for NM_006218.4:c.2937-15T>C.
BP4	Not met	VCEP BP4 applies to intronic positions (except canonical splice sites) and requires two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact on splicing. SpliceAI predicts no significant splice impact (max delta = 0.17), but varSEAK and MaxEntScan data are unavailable. With only one of three tools available, the two-of-three threshold is not met.	spliceai cspec
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No evidence of an alternate molecular diagnosis co-occurring with NM_006218.4:c.2937-15T>C is available.
BP6	N/A	BP6 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Not met	VCEP BP7 applies to intronic positions (except canonical splice sites) and requires the nucleotide to be non-conserved (PhyloP score <0.1). A PhyloP conservation score is not available for this position. Without the PhyloP score, the criterion cannot be applied.	cspec

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