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PIK3CAc.1930T>CUncertain significance
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Variant interpretation report

PIK3CA c.1930T>C, p.(Tyr644His)

NM_006218.4:c.1930T>C NP_006209.2:p.(Tyr644His) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PIK3CA

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen PIK3CA VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,607,506 alleles

gnomAD v4.1: 1 / 1,607,506 alleles. Recorded AF 6.22082e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 5 not met · 8 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

Tyr644 lies outside the PIK3CA Table 4 PM1 domains (amino acids 322-483 and 797-1068), so domain-based PM1 support was not established.

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.

Met · 1

PM2 SupportingThis 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. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM2: Supporting if absent/rare in controls with one person maximum.
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: 1 allele
  • AF 6.22082e-07
  • 0 homozygotes.
  • The VCEP permits PM2 at Supporting strength with one person maximum.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Not met · 5 · evaluated, threshold not reached

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. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS4 uses Table 2A/2B point thresholds and requires PM2.
Evidence considered
  • PS4 under this VCEP is point-based and requires PM2 first.
  • No ClinVar observations or literature cases were identified to contribute phenotype points.
Sources
cspec ↗clinvar ↗
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). Tyr644 lies outside these intervals, and Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM1 is Supporting only for listed Table 4 domains.
Evidence considered
  • Approved PIK3CA PM1 domains are aa 322-483 and aa 797-1068.
  • The variant protein consequence is p.Tyr644His.
  • Cancer Hotspots review did not identify a significant hotspot.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1hotspots ↗
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. Details ▾Hide ▴
Rule
Brain Malformations VCEP BA1 threshold: >0.0926%.
Evidence considered
  • gnomAD v4.1 total AF 6.22082e-07.
  • BA1 threshold is >0.0926%.
Sources
gnomad_v4 ↗cspec ↗
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. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS1 threshold: >0.0185%.
Evidence considered
  • gnomAD v4.1 total AF 6.22082e-07.
  • BS1 threshold is >0.0185%.
Sources
gnomad_v4 ↗cspec ↗
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. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS2 requires >=3 qualifying observations.
Evidence considered
  • gnomAD v4.1 shows 0 homozygotes.
  • No qualifying unaffected family data were identified.
  • The VCEP requires at least 3 homozygotes or 3 well-phenotyped heterozygous family members.
Sources
gnomad_v4 ↗cspec ↗

Not assessed · 8 · no assessment recorded

PS1 No previously established pathogenic variant causing the same amino acid change was identified in the available records, so PS1 could not be confirmed. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant.
Evidence considered
  • ClinVar had no record for this variant.
  • The available same-residue comparator artifact did not yield a usable comparator determination.
Still missing
  • A validated same-amino-acid pathogenic comparator was not identified.
Sources
clinvar ↗pm5_candidates
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. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS2 requires confirmed parental absence and/or specified tissue mosaicism evidence.
Evidence considered
  • The Brain Malformations VCEP requires confirmed parental absence and/or tissue mosaicism evidence for PS2.
Still missing
  • No maternity/paternity-confirmed parental studies were identified.
  • No affected-tissue versus other-tissue allele fraction data were identified.
Sources
cspec ↗
PS3 No validated variant-specific functional study meeting the Brain Malformations VCEP requirements was identified, so PS3 was not applied. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS3 follows SVI functional assay requirements with panel-specific specifications.
Evidence considered
  • The Brain Malformations VCEP requires validated functional evidence.
  • OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
  • No acceptable variant-specific functional assay was identified.
Sources
cspec ↗oncokb ↗
PM5 No established pathogenic missense comparator at the same residue was confirmed from the available records, so PM5 could not be applied. Details ▾Hide ▴
Rule
PM5 requires a different pathogenic missense change at the same residue.
Evidence considered
  • No ClinVar record was identified for this variant.
  • The available PM5 candidate collection did not provide a confirmed usable comparator.
Still missing
  • A confirmed same-residue pathogenic comparator was not identified.
Sources
pm5_candidatesclinvar ↗
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. Details ▾Hide ▴
Rule
Brain Malformations VCEP PP2: award if missense constraint z-score > 3.09.
Evidence considered
  • The VCEP defines a z-score threshold of greater than 3.09 for PP2 in PIK3CA.
Still missing
  • The required missense constraint z-score was not provided.
Sources
cspec ↗
BS3 No well-established benign functional study showing normal effect for this variant was identified, so BS3 was not applied. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS3 follows SVI functional assay requirements with panel-specific specifications.
Evidence considered
  • The Brain Malformations VCEP requires validated benign functional evidence for BS3.
  • OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
  • No acceptable benign functional assay was identified.
Sources
cspec ↗oncokb ↗
BP2 No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP2: observed in cis or trans with a known pathogenic variant.
Evidence considered
  • The VCEP allows BP2 when a variant is observed in cis or trans with a known pathogenic variant.
Still missing
  • No phase data with a known pathogenic PIK3CA variant were identified.
Sources
cspec ↗
BP5 No evidence was identified showing an alternate molecular explanation for the phenotype independent of this variant, so BP5 was not applied. Details ▾Hide ▴
Rule
BP5 applies when an alternate molecular basis for disease is established.
Evidence considered
  • The VCEP retains BP5 without modification.
Still missing
  • No alternate molecular diagnosis data were identified.
Sources
cspec ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe Brain Malformations VCEP considers PVS1 not applicable for PIK3CA because the disease mechanism is gain of function rather than loss of function. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PVS1 not applicable for PIK3CA.
Evidence considered
  • PIK3CA is evaluated under the Brain Malformations VCEP specification.
  • The specification states that PVS1 is not applicable for this gene.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM3 VCEPPM3 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PM3 not applicable.
Evidence considered
  • The VCEP marks PM3 not applicable.
Sources
cspec ↗
PM4 VCEPPM4 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PM4 not applicable.
Evidence considered
  • The VCEP marks PM4 not applicable.
Sources
cspec ↗
PM6 VCEPPM6 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PM6 not applicable.
Evidence considered
  • The VCEP marks PM6 not applicable.
Sources
cspec ↗
PP1 VCEPPP1 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PP1 not applicable.
Evidence considered
  • The VCEP marks PP1 not applicable.
Sources
cspec ↗
PP3 VCEPPP3 is not applicable under the Brain Malformations VCEP for this variant type. Computational scores were available, including REVEL 0.613, BayesDel 0.183264, and SpliceAI max delta score 0.02, but they are not used to apply PP3 in this PIK3CA framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PP3 not applicable.
Evidence considered
  • The VCEP marks PP3 not applicable.
  • REVEL score 0.613.
  • BayesDel score 0.183264.
  • SpliceAI max delta score 0.02.
Sources
cspec ↗revelbayesdelspliceai ↗
PP4 VCEPPP4 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PP4 not applicable.
Evidence considered
  • The VCEP marks PP4 not applicable.
Sources
cspec ↗
PP5 VCEPPP5 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PP5 not applicable.
Evidence considered
  • The VCEP marks PP5 not applicable.
Sources
cspec ↗
BS4 VCEPBS4 is not applicable under the Brain Malformations VCEP because these disorders are typically de novo, germline mosaic, or post-zygotic. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: BS4 not applicable.
Evidence considered
  • The VCEP marks BS4 not applicable.
Sources
cspec ↗
BP1 VCEPBP1 is not applicable for PIK3CA in this VCEP because the disease mechanism is gain of function. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: BP1 not applicable.
Evidence considered
  • The VCEP marks BP1 not applicable for this framework.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 VCEPBP3 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: BP3 not applicable.
Evidence considered
  • The VCEP marks BP3 not applicable.
Sources
cspec ↗
BP4 N/ABP4 is limited by the Brain Malformations VCEP to synonymous, intronic, or non-coding variants with no predicted splice impact, so it is not applicable to this missense variant. SpliceAI predicts no significant splice impact with a max delta score of 0.02, but that does not make BP4 applicable here. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP4 is not applicable to missense variants.
Evidence considered
  • The VCEP restricts BP4 to synonymous
  • intronic
  • and non-coding variants.
  • SpliceAI max delta score 0.02.
Sources
cspec ↗spliceai ↗
BP6 VCEPBP6 is not applicable under the Brain Malformations VCEP for this disease framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: BP6 not applicable.
Evidence considered
  • The VCEP marks BP6 not applicable.
Sources
cspec ↗
BP7 N/ABP7 is restricted by the Brain Malformations VCEP to synonymous, intronic, or non-coding variants and is not applicable to this missense variant. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP7 is not applicable to missense variants.
Evidence considered
  • The VCEP restricts BP7 to synonymous
  • intronic
  • or non-coding variants.
Sources
cspec ↗

Identifiers

Gene
PIK3CA
Transcript
NM_006218.4
Coding (HGVS c.)
NM_006218.4:c.1930T>C
Protein (HGVS p.)
NP_006209.2:p.(Tyr644His)
GRCh38
chr3:179219967 T>C
GRCh37
chr3:178937755 T>C

Gene diagram

Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.

PIK3CANM_006218.4
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,607,506 alleles AF 6.22e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,607,506 alleles · 0 hom
European (non-Finnish)1 / 1,177,588 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

SpliceAI and Pangolin

SpliceAI acceptor lossat -67 bp
0.020
SpliceAI acceptor gainat -18 bp
0.010
SpliceAI donor lossat -232 bp
0.000
SpliceAI donor gainat +85 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.060

Other predictors

REVEL
0.613
BayesDel
0.183

How the predictions were used

PP3 VCEPPP3 is not applicable under the Brain Malformations VCEP for this variant type. Computational scores were available, including REVEL 0.613, BayesDel 0.183264, and SpliceAI max delta score 0.02, but they are not used to apply PP3 in this PIK3CA framework. Details ▾Hide ▴
VCEP rule
Brain Malformations VCEP: PP3 not applicable.
Evidence considered
  • The VCEP marks PP3 not applicable.
  • REVEL score 0.613.
  • BayesDel score 0.183264.
  • SpliceAI max delta score 0.02.
Sources
cspec ↗revelbayesdelspliceai ↗
BP4 N/ABP4 is limited by the Brain Malformations VCEP to synonymous, intronic, or non-coding variants with no predicted splice impact, so it is not applicable to this missense variant. SpliceAI predicts no significant splice impact with a max delta score of 0.02, but that does not make BP4 applicable here. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP4 is not applicable to missense variants.
Evidence considered
  • The VCEP restricts BP4 to synonymous
  • intronic
  • and non-coding variants.
  • SpliceAI max delta score 0.02.
Sources
cspec ↗spliceai ↗
BP7 N/ABP7 is restricted by the Brain Malformations VCEP to synonymous, intronic, or non-coding variants and is not applicable to this missense variant. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP7 is not applicable to missense variants.
Evidence considered
  • The VCEP restricts BP7 to synonymous
  • intronic
  • or non-coding variants.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.613. BayesDel score = 0.183264.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,607,506 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.