The PIK3CA c.1173A>G (p.Ile391Met) variant has been reported in ClinVar as Benign, including a Benign expert-panel classification from the ClinGen Brain Malformations Variant Curation Expert Panel.1 This variant is common in population databases, with allele frequency 6.57058% in gnomAD v2.1 and 6.60819% in gnomAD v4.1, greatly exceeding the VCEP BA1 threshold of 0.0926% and BS1 threshold of 0.0185%, and it is also observed in numerous homozygous individuals.2 Curated literature resources identified functional publications relevant to this variant, but the retrieved evidence did not provide validated variant-specific assay results sufficient to apply either PS3 or BS3.3 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, while REVEL is 0.236 and BayesDel is -0.391355; however, PP3 is not applicable and BP4 is restricted to non-missense variants in this VCEP framework.4
Final classification
Benign
PM1BS2BA1BP6BS1
PIK3CA
c.1173A>G
p.Ile391Met
This variant
The PIK3CA c.1173A>G (p.Ile391Met) variant has been reported in ClinVar as Benign, including a Benign expert-panel classification from the ClinGen Brain Malformations Variant Curation Expert Panel.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: BS2 strong (-4) + PM1 supporting (+1) + BA1 stand-alone benign (-8) + BS1 strong (-4) = -15 points, which maps to Benign.
Classification rationale
PM1
BS2BA1BP6BS1
Benign
PIK3CA c.1173A>G
PM1 + BS2 + BA1 + BP6 + BS1
→
Benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
PM1
supporting
review
Pathogenic
The p.Ile391Met change lies within the PIK3CA amino-acid interval 322-483, which is listed by this VCEP as an approved Table 4 critical functional domain, supporting PM1 at Supporting strength. Cancer Hotspots did not identify a statistically significant hotspot at residue 391, but hotspot recurrence is not required by this VCEP when the variant falls in an approved domain.
Variant protein consequence p.Ile391MetVCEP Table 4 domain interval 322-483 for PIK3CACancer Hotspots showed no significant hotspot row
BA1
stand-alone
Benign
This variant exceeds the VCEP BA1 threshold of greater than 0.0926% by a wide margin, with overall allele frequency 6.57058% in gnomAD v2.1 and 6.60819% in gnomAD v4.1.
VCEP BA1 threshold >0.0926%gnomAD v2.1 AF 0.0657058gnomAD v4.1 AF 0.0660819
BS1
strong
Benign
This variant exceeds the VCEP BS1 threshold of greater than 0.0185%, with overall allele frequency 6.57058% in gnomAD v2.1 and 6.60819% in gnomAD v4.1, which is far above the maximum expected frequency for a disease-causing PIK3CA brain malformation variant.
VCEP BS1 threshold >0.0185%gnomAD v2.1 AF 0.0657058gnomAD v4.1 AF 0.0660819
BS2
strong
Benign
This variant is present in many apparently healthy population participants, including 1,032 homozygotes in gnomAD v2.1 and 4,921 homozygotes in gnomAD v4.1, which is well above the VCEP BS2 threshold of at least 3 homozygotes.
gnomAD v2.1 homozygotes = 1032gnomAD v4.1 homozygotes = 4921VCEP BS2 threshold >=3 homozygotes
Assessed · not applied
· 2 not met · 8 not assessed
Pathogenic
PS1
No independently verified evidence was identified showing that this variant causes the same amino acid change as a previously established pathogenic PIK3CA variant by a different nucleotide substitution.
PS2
No confirmed de novo evidence with parental testing and tissue-distribution data was identified for this variant, so the VCEP PS2 requirements were not met from the retrieved evidence.
PS3
Curated literature resources identified functional publications relevant to this variant, but the retrieved evidence did not provide validated variant-specific assay results sufficient to support a damaging effect under the VCEP PS3 requirements.
PS4
PS4 is not met because this VCEP requires PM2 before phenotype-point assignment, and this variant is common in population databases rather than rare or absent from controls.
PM2
PM2 is not met because this variant is not rare in population databases.
PM5
No independently verified evidence was identified showing that a different missense change at residue Ile391 has been established as pathogenic.
PP2
PP2 could be considered for PIK3CA missense variants in this VCEP, but no gene-level missense constraint z-score was provided in the retrieved evidence to compare with the required threshold of greater than 3.09.
Benign
BS3
Curated literature resources identified functional publications relevant to this variant, but the retrieved evidence did not provide validated variant-specific studies demonstrating a normal or no-damaging effect sufficient for BS3.
BP2
No phase data were identified showing that this variant was observed in cis or trans with a known pathogenic PIK3CA variant.
BP5
No independently verified evidence was identified showing that this variant was found in a case with an alternate molecular basis that explains the reported phenotype.
N/A · 13
PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.0660819; MAF= 6.60819%, 106360/1609518 alleles, homozygotes = 4921) and has highest observed frequency in the African/African American population (AF= 0.211487; MAF= 21.14870%, 15815/74780 alleles, homozygotes = 1715); grpmax FAF= 0.208728.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0657058; MAF= 6.57058%, 18372/279610 alleles, homozygotes = 1032) and has highest observed frequency in the African/African American population (AF= 0.211283; MAF= 21.12834%, 5097/24124 alleles, homozygotes = 531); grpmax FAF= 0.204728.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.6%
· 106360 / 1,609,518
4921 hom · FAF 21%
4921 hom · FAF 21%
African/African American 15815 / 74,780 |
21% 1715 hom |
Middle Eastern 849 / 6,052 |
14% 64 hom |
Ashkenazi Jewish 3823 / 29,530 |
13% 235 hom |
Amish 74 / 912 |
8.1% 2 hom |
Remaining individuals 4887 / 62,294 |
7.8% 222 hom |
European (non-Finnish) 73750 / 1,176,896 |
6.3% 2466 hom |
Admixed American 3717 / 59,832 |
6.2% 153 hom |
European (Finnish) 1679 / 63,916 |
2.6% 24 hom |
South Asian 1761 / 90,564 |
1.9% 40 hom |
East Asian 5 / 44,742 |
0.011% |
gnomAD v2.1
6.6%
· 18372 / 279,610
1032 hom · FAF 20%
1032 hom · FAF 20%
African/African American 5097 / 24,124 |
21% 531 hom |
Ashkenazi Jewish 1360 / 10,350 |
13% 85 hom |
Remaining individuals 554 / 7,090 |
7.8% 27 hom |
European (non-Finnish) 8298 / 128,344 |
6.5% 299 hom |
Admixed American 1857 / 34,884 |
5.3% 65 hom |
European (Finnish) 621 / 25,020 |
2.5% 11 hom |
South Asian 585 / 30,324 |
1.9% 14 hom |
+ 1 not observed (East Asian)
ClinVar
This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Benign by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.236. BayesDel score = -0.391355.
Functional
Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55885079, n = 104 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links