PM2_Supporting: This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP threshold of ≤1 individual in population databases.1 PP2_Supporting: PIK3CA has a missense constraint Z-score of 4.07 in gnomAD v2.1, exceeding the VCEP threshold of >3.09, indicating a low rate of benign missense variation.2 PS1 is not met: no alternative nucleotide change at codon 681 producing p.Ser681Thr has been established as pathogenic.3 PM1 is not met: residue Ser681 at position 681 falls outside the VCEP Table 4 approved kinase domains for PIK3CA (AA 322-483 and AA 797-1068).4 PS3 and BS3 are not met: no variant-specific functional studies are available. OncoKB classifies p.Ser681Thr as Unknown Oncogenic Effect.5 PS4 is not met: no affected individuals with this variant have been reported; no phenotype points can be scored under VCEP Tables 2A/2B.6 Six publications were reviewed; none mention NM_006218.4:c.2042G>C or PIK3CA p.Ser681Thr.7 Using the Brain Malformations VCEP Tavtigian point framework (Path Supporting +1, Path Moderate +2, Path Strong +4, Path Very Strong +8; Benign Supporting -1, Mod -2, Strong -4, Very Strong -8), the total score is +2 (PM2_Supporting +1, PP2_Supporting +1), which falls within the VUS range (0-5 points).8
PIK3CA
Final classification
VUS
PM2PP2
PIK3CA
c.2042G>C
p.Ser681Thr
This variant
PM2_Supporting: This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP threshold of ≤1 individual in population databases.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM2 supporting (+1) + PP2 supporting (+1) = 2 points, which maps to VUS.
Classification rationale
PM2PP2
VUS
PIK3CA c.2042G>C
PM2 + PP2
→
VUS
Gene diagram
· NM_006218.4 · variants mapped to exon structure
PIK3CA
NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Per VCEP specification, PM2 is awarded at Supporting strength when the variant is absent or present in ≤1 individual in population databases.
gnomAD v2.1: absent (AF = 0AC = 0). gnomAD v4.1: absent (AF = 0AC = 0). gnomAD-Canada v1.0: absent (AF = 0
✓
PP2
supporting
Pathogenic
PIK3CA has a missense constraint Z-score of 4.07 in gnomAD v2.1, exceeding the VCEP threshold of >3.09. This indicates a low rate of benign missense variation in PIK3CA, where missense variants are a common disease mechanism.
gnomAD v2.1 missense constraint: Z-score = 4.07 (o/e = 0.509). VCEP threshold: Z > 3.09. PIK3CA is among the genes for which PP2 is applicable (MTORPIK3CAAKT3).
Assessed · not applied
· 12 not met · 0 not assessed
Pathogenic
PS1
No other nucleotide change at codon 681 producing the same amino acid substitution (p.Ser681Thr) has been established as pathogenic.
PS2
No de novo observation reported for this variant in any available source.
PS3
No well-established in vitro or in vivo functional studies have been performed for this specific variant.
PS4
No affected individuals with this variant have been reported in the literature or clinical databases.
PM1
Residue Ser681 (amino acid position 681) does not fall within the Table 4 critical functional domains for PIK3CA.
PM5
No pathogenic or likely pathogenic missense variant at the same amino acid residue (Ser681) was identified as a comparator.
Benign
BA1
Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No homozygotes are present in gnomAD and no well-phenotyped heterozygous family members have been reported.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this specific variant.
BP2
No evidence that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA.
BP5
No evidence that this variant has been found in a case with an alternate molecular basis for disease.
N/A · 11
PVS1 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1038606)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.235. BayesDel score = -0.0427925.
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
9Sources
Triaged references · 6 PMIDs not cited in assessment
23652378 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
CLINVAR
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
22947299 ↗
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
CLINVAR
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR