Classification rationale

VUS

PIK3CA c.2937-15T>C

NM_006218.4:c.2937-15T>C is an intronic variant in PIK3CA located 15 bases upstream of exon 20. 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.¹ 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.² 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.³

1 cspec ↗final_classification_framework

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗final_classification_framework

Gene diagram · NM_006218.4 · variants mapped to exon structure

PIK3CA NM_006218.4

Fetching transcript structure from UCSC…

Applied criteria · 0 applied · 13 assessed

Applied · 0

No criteria were applied for this variant.

Assessed · not applied

Pathogenic

PS2 No de novo evidence is available for NM_006218.4:c.2937-15T>C.

PS3 No well-established in vitro or in vivo functional studies are available for NM_006218.4:c.2937-15T>C.

PS4 No affected individuals with brain malformation phenotypes have been reported for NM_006218.4:c.2937-15T>C in the reviewed literature.

PM1 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).

PM2 VCEP PM2_Supporting requires the variant to be absent or rare from controls with at most one individual (≤1) in an ethnically-matched cohort.

Benign

BA1 VCEP BA1 requires an allele frequency above 0.0926%.

BS1 VCEP BS1 requires an allele frequency above 0.0185%.

BS2 VCEP BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous individuals in well-phenotyped family members.

BS3 No well-established in vitro or in vivo functional studies demonstrate a neutral effect for NM_006218.4:c.2937-15T>C.

BP2 BP2 requires observation of the variant in cis or trans with a known pathogenic variant in the same gene.

BP4 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.

BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease.

BP7 VCEP BP7 applies to intronic positions (except canonical splice sites) and requires the nucleotide to be non-conserved (PhyloP score <0.1).

N/A · 12 PVS1 · PS1 · PM5 · PM6 · PP1 · PP2 · PP3 · PP4 · PP5 · BS4 · BP1 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.13851e-05; MAF= 0.00914%, 145/1586692 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000115425; MAF= 0.01154%, 134/1160924 alleles, homozygotes = 0); grpmax FAF= 9.935e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 6.25732e-05; MAF= 0.00626%, 17/271682 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000117495; MAF= 0.01175%, 4/34044 alleles, homozygotes = 0); grpmax FAF= 5.237e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00021715526601520088, 4/18420 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0091% · 145 / 1,586,692
0 hom · FAF 0.0099%

European (non-Finnish) 134 / 1,160,924	0.012%
Ashkenazi Jewish 3 / 28,698	0.01%
Admixed American 3 / 58,596	0.0051%
Remaining individuals 3 / 61,278	0.0049%
African/African American 2 / 74,156	0.0027%

+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian)

gnomAD v2.1

0.0063% · 17 / 271,682
0 hom · FAF 0.0052%

Admixed American 4 / 34,044	0.012%
Ashkenazi Jewish 1 / 9,542	0.01%
European (non-Finnish) 12 / 125,156	0.0096%

+ 5 not observed (African/African American, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

0.022% · 4 / 18,420
0 hom · FAF 0.012%

European (non-Finnish)

4 / 11,740

0.034%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1602491)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 6 PMIDs not cited in assessment

23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR

25190698 ↗ Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. CLINVAR

26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?