About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2042G>C, p.(Ser681Thr)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP2Supporting
PP2 · supporting
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.
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) + PP2 supporting (+1) = 2 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
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
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 13 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
PS1 is not met: no alternative nucleotide change at codon 681 producing p.Ser681Thr has been established as pathogenic.
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).
PS3 and BS3 are not met: no variant-specific functional studies are available. OncoKB classifies p.Ser681Thr as Unknown Oncogenic Effect.
PS4 is not met: no affected individuals with this variant have been reported; no phenotype points can be scored under VCEP Tables 2A/2B.
Six publications were reviewed; none mention NM_006218.4:c.2042G>C or PIK3CA p.Ser681Thr.
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).
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0
- AC = 0). gnomAD v4.1: absent (AF = 0
- AC = 0). gnomAD-Canada v1.0: absent (AF = 0
- AC = 0).
Sources
PP2 SupportingPIK3CA 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. Details ▾Hide ▴
Evidence considered
- 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 (MTOR
- PIK3CA
- AKT3).
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No other nucleotide change at codon 681 producing the same amino acid substitution (p.Ser681Thr) has been established as pathogenic. This variant represents a novel missense change at this residue. Details ▾Hide ▴
Evidence considered
- ClinVar (VariationID 1038606) does not list any other nucleotide change at this codon producing p.Ser681Thr with a pathogenic classification. No alternative nucleotide change yielding the same amino acid substitution was identified.
Sources
PS2 No de novo observation reported for this variant in any available source. No evidence of absent parental genotype or tissue-specific mosaicism as required by the VCEP PS2 criteria. Details ▾Hide ▴
Evidence considered
- ClinVar contains no de novo submissions. No literature reports describing de novo occurrence were identified among the six reviewed publications.
Still missing
- No proband-level data available to assess de novo status.
Sources
PS3 No well-established in vitro or in vivo functional studies have been performed for this specific variant. OncoKB classifies this variant as Unknown Oncogenic Effect. No functional assay meeting SVI/BMVCEP quality criteria (PMID:31892348) was identified. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect. COSMIC: no somatic occurrences. No published functional studies for p.Ser681Thr identified among reviewed publications.
Still missing
- No variant-specific functional data available. Functional characterization of p.Ser681Thr would be needed to assess this criterion.
Sources
PS4 No affected individuals with this variant have been reported in the literature or clinical databases. No phenotype points can be assigned under VCEP Tables 2A/2B. While PM2 is met (absent from controls), no cases exist to score. Details ▾Hide ▴
Evidence considered
- ClinVar: no case-level phenotype data. COSMIC: no somatic occurrences. No published case reports identified among six reviewed publications.
Still missing
- No affected individuals with this variant identified. Phenotype points cannot be assigned without cases.
Sources
PM1 Residue Ser681 (amino acid position 681) does not fall within the Table 4 critical functional domains for PIK3CA. The VCEP-approved domains are the kinase domains at AA 322-483 and AA 797-1068. Ser681 lies between these two domains and is not within a mutational hotspot. Details ▾Hide ▴
Evidence considered
- VCEP Table 4: PIK3CA kinase domains are AA 322-483 and AA 797-1068. Ser681 at position 681 is outside both domains. Cancer Hotspots: residue not significant.
Sources
PM5 No pathogenic or likely pathogenic missense variant at the same amino acid residue (Ser681) was identified as a comparator. The PM5 candidate search returned zero same-residue candidates, including zero expert-panel-reviewed pathogenic variants at position 681. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- 0 expert-panel PLP candidates
- 0 non-expert majority PLP candidates.
Still missing
- No pathogenic comparators at residue 681.
Sources
pm5_candidatesclinvar ↗
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The VCEP BA1 threshold is >0.0926% allele frequency. This variant's population frequency is 0%, far below the threshold. Details ▾Hide ▴
Evidence considered
- All gnomAD populations: AF = 0. VCEP BA1 threshold: >0.0926%. Not met.
Sources
BS1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The VCEP BS1 threshold is >0.0185% allele frequency. This variant's population frequency is 0%, far below the threshold. Details ▾Hide ▴
Evidence considered
- All gnomAD populations: AF = 0. VCEP BS1 threshold: >0.0185%. Not met.
Sources
BS2 No homozygotes are present in gnomAD and no well-phenotyped heterozygous family members have been reported. The VCEP requires ≥3 homozygotes in gnomAD or ≥3 well-phenotyped heterozygous family members. Details ▾Hide ▴
Evidence considered
- gnomAD: 0 homozygotes across all datasets. No family member data available.
Still missing
- No family-level data available.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this specific variant. Functional evidence for p.Ser681Thr is absent from the literature and curated databases. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No functional studies identified in reviewed publications.
Still missing
- No variant-specific functional data available.
Sources
BP2 No evidence that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA. No phase information is available. Details ▾Hide ▴
Evidence considered
- No cis/trans phase data available from ClinVar or literature.
Still missing
- No phase information available.
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. No co-occurring explanatory variant has been reported. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis identified in any reviewed source.
Still missing
- No case-level genotype data available.
PS5 PS5 is not included in the Brain Malformations VCEP specification. Under generic ACMG/AMP 2015 rules, PS5 requires a reputable source to have recently reported the variant as pathogenic. ClinVar classifies this variant as Uncertain Significance (2 clinical laboratories), which does not satisfy the criterion. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- criteria provided
- single submitter. No reputable source reports the variant as pathogenic.
Sources
clinvar ↗generic_acmg_combination_rules
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: loss of function is not the disease mechanism; PIK3CA-related brain malformations are caused by gain-of-function variants. Details ▾Hide ▴
Evidence considered
- VCEP specification explicitly states PVS1 is not applicable because the disease mechanism is gain of function.
Sources
PM6 VCEPNot applicable per ClinGen Brain Malformations VCEP: this point is addressed according to PS2 and will not be used. Additionally, no assumed de novo events were identified. Details ▾Hide ▴
Evidence considered
- VCEP specification states PM6 is addressed under PS2 and will not be used independently.
Sources
PP1 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: disease-causing variants are germline mosaic, de novo, or mosaic, making co-segregation analysis inapplicable. Details ▾Hide ▴
Evidence considered
- VCEP specification: PP1 is not applicable since disease-causing variants are germline mosaic
- de novo or mosaic.
Sources
PP3 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas PIK3CA-related brain malformations are caused by gain-of-function variants. Use may be revisited when algorithms specifically designed for GOF prediction become available. Details ▾Hide ▴
Evidence considered
- VCEP specification: PP3 is not applicable since these variants are GOF and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.
Sources
PP4 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: this criterion is accounted for under PS4 in the VCEP framework. Details ▾Hide ▴
Evidence considered
- VCEP specification: PP4 is not applicable since this criterion is accounted for under PS4.
Sources
PP5 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP specification: PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
BS4 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: not applicable as these are de novo, germline mosaic, or post-zygotic mutations. Details ▾Hide ▴
BP1 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: loss of function is not the disease mechanism for PIK3CA-related brain malformations. Details ▾Hide ▴
Evidence considered
- VCEP specification: BP1 is not applicable as LOF is not the disease mechanism.
Sources
BP4 N/ANot applicable per ClinGen Brain Malformations VCEP v1.1.0: BP4 is restricted to synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.2042G>C, p.Ser681Thr). Details ▾Hide ▴
Evidence considered
- VCEP BP4 rule: applicable only for synonymous
- intronic (except canonical splice sites)
- and non-coding UTR variants. This variant is a missense substitution.
Sources
BP6 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP specification: BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
BP7 N/ANot applicable per ClinGen Brain Malformations VCEP v1.1.0: BP7 is restricted to synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.2042G>C, p.Ser681Thr). Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule: applicable only for synonymous
- intronic (except canonical splice sites)
- and non-coding UTR variants. This variant is a missense substitution.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.2042G>C
- Protein (HGVS p.)
- NP_006209.2:p.(Ser681Thr)
- GRCh38
- chr3:179221012 G>C
- GRCh37
- chr3:178938800 G>C
- ClinVar
- 1038606
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.235
- BayesDel
- -0.043
How the predictions were used
PP3 VCEPNot applicable per ClinGen Brain Malformations VCEP v1.1.0: traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas PIK3CA-related brain malformations are caused by gain-of-function variants. Use may be revisited when algorithms specifically designed for GOF prediction become available. Details ▾Hide ▴
Evidence considered
- VCEP specification: PP3 is not applicable since these variants are GOF and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.
Sources
BP4 N/ANot applicable per ClinGen Brain Malformations VCEP v1.1.0: BP4 is restricted to synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.2042G>C, p.Ser681Thr). Details ▾Hide ▴
Evidence considered
- VCEP BP4 rule: applicable only for synonymous
- intronic (except canonical splice sites)
- and non-coding UTR variants. This variant is a missense substitution.
Sources
BP7 N/ANot applicable per ClinGen Brain Malformations VCEP v1.1.0: BP7 is restricted to synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.2042G>C, p.Ser681Thr). Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule: applicable only for synonymous
- intronic (except canonical splice sites)
- and non-coding UTR variants. This variant is a missense substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.235. BayesDel score = -0.0427925.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.Discusses a framework for neonatal screening policies in the European Union. NM_006218.4:c.2042G>C (PIK3CA p.Ser681Thr) was not identified in this paper.Does not name this variant
-
PMID 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.Joint statement on expanded carrier screening in reproductive medicine from ACMG, ACOG, NSGC, and other organizations. NM_006218.4:c.2042G>C (PIK3CA p.Ser681Thr) was not identified in this paper.Does not name this variant
-
PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ summary on genetics of breast and gynecologic cancers. No abstract content available. NM_006218.4:c.2042G>C (PIK3CA p.Ser681Thr) was not identified in the available metadata.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Describes the Sherloc variant classification framework, a refinement of ACMG-AMP guidelines. NM_006218.4:c.2042G>C (PIK3CA p.Ser681Thr) was not identified in this paper.Does not name this variant
-
PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.Langer A et al. · 2012Guidelines for assessing methodological quality of economic evaluations of newborn screening. NM_006218.4:c.2042G>C (PIK3CA p.Ser681Thr) was not identified in this paper.Does not name this variant
-
PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.Guidelines for parental permission in pilot newborn screening research from the NBSTRN. NM_006218.4:c.2042G>C (PIK3CA p.Ser681Thr) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
2 Uncertain significance
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1038606/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178938800-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179221012-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179221012-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.2042…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/S681T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.2042G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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.