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
PIK3CA
Final classification
Benign
PIK3CA c.1173A>G · p.Ile391Met
PIK3CA
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
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 5 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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