The PIK3CA c.1930T>C (p.Tyr644His) variant has not been reported in ClinVar, and Cancer Hotspots did not identify a statistically significant hotspot at Tyr644 in the reviewed record.1 This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,607,506 alleles; AF 6.22082e-07; 0 homozygotes), which satisfies PM2_Supporting under the Brain Malformations VCEP and is far below the BA1 and BS1 population thresholds.2 Tyr644 lies outside the PIK3CA Table 4 PM1 domains (amino acids 322-483 and 797-1068), so domain-based PM1 support was not established.3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.02); REVEL 0.613 and BayesDel 0.183264 were available, but PP3 and BP4 are not applicable to this missense variant under the Brain Malformations VCEP.4
Final classification
VUS
PM2
PIK3CA
c.1930T>C
p.Tyr644His
This variant
The PIK3CA c.1930T>C (p.Tyr644His) variant has not been reported in ClinVar, and Cancer Hotspots did not identify a statistically significant hotspot at Tyr644 in the reviewed record.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.
Classification rationale
PM2
VUS
PIK3CA c.1930T>C
PM2
→
VUS
3
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
4
spliceai ↗revelbayesdelcspec ↗
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_006218.4 · variants mapped to exon structure
PIK3CA
NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 13 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,607,506 alleles; AF 6.22082e-07; 0 homozygotes), which is within the Brain Malformations VCEP allowance of one person maximum for PM2_Supporting.
gnomAD v2.1: absent.gnomAD v4.1: 1 alleleAF 6.22082e-07
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No previously established pathogenic variant causing the same amino acid change was identified in the available records, so PS1 could not be confirmed.
PS2
No confirmed de novo data, parental testing results, or tissue-specific allele fraction data were identified for this variant, so PS2 could not be applied.
PS3
No validated variant-specific functional study meeting the Brain Malformations VCEP requirements was identified, so PS3 was not applied.
PS4
Although PM2 is satisfied, no affected-case point evidence meeting the Brain Malformations VCEP PS4 scoring framework was identified for this variant, so PS4 is not met.
PM1
The Brain Malformations VCEP allows PM1 only as Supporting for variants within approved PIK3CA Table 4 domains (amino acids 322-483 or 797-1068).
PM5
No established pathogenic missense comparator at the same residue was confirmed from the available records, so PM5 could not be applied.
PP2
The Brain Malformations VCEP allows PP2 for PIK3CA only when the missense constraint z-score is greater than 3.09, but that gene-level value was not available in the reviewed evidence, so PP2 was not assessed.
Benign
BA1
The highest observed population frequency is 6.22082e-07 in gnomAD v4.1 (0.00006%), which is far below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%, so BA1 is not met.
BS1
The highest observed population frequency is 6.22082e-07 in gnomAD v4.1 (0.00006%), which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%, so BS1 is not met.
BS2
This variant has 0 homozygotes in gnomAD and no well-phenotyped unaffected family observations were identified, so the Brain Malformations VCEP BS2 requirement of at least 3 qualifying observations is not met.
BS3
No well-established benign functional study showing normal effect for this variant was identified, so BS3 was not applied.
BP2
No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed.
BP5
No evidence was identified showing an alternate molecular explanation for the phenotype independent of this variant, so BP5 was not applied.
N/A · 14
PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.22082e-07; MAF= 0.00006%, 1/1607506 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.49193e-07; MAF= 0.00008%, 1/1177588 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,607,506
0 hom
0 hom
European (non-Finnish) 1 / 1,177,588 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.613. BayesDel score = 0.183264.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links