Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg)

CA130467

39703 (ClinVar)

Gene: PIK3CA
Condition: cerebral malformation
Inheritance Mode: Autosomal dominant inheritance (mosaic)
Link to MONDO
UUID: 857fcdd5-3e4e-4d8c-bc86-6586a8591ded
Approved on: 2021-01-31
Published on: 2021-09-27

HGVS expressions

NM_006218.3:c.2740G>A
NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg)
NC_000003.12:g.179230077G>A
CM000665.2:g.179230077G>A
NC_000003.11:g.178947865G>A
CM000665.1:g.178947865G>A
NC_000003.10:g.180430559G>A
NG_012113.2:g.86555G>A
ENST00000263967.4:c.2740G>A
ENST00000462255.2:n.1763G>A
ENST00000643187.1:c.2740G>A
ENST00000674534.1:n.3648G>A
ENST00000674622.1:c.1161G>A
ENST00000675467.1:n.5547G>A
ENST00000675786.1:c.*1307G>A
ENST00000675796.1:n.2635G>A
ENST00000263967.3:c.2740G>A
NM_006218.2:c.2740G>A
NM_006218.4:c.2740G>A
More

Pathogenic

Met criteria codes 5
PM1_Supporting PM2 PS2 PS4 PP2
Not Met criteria codes 21
BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 BA1 PM6 PVS1 PM3 PM5 PM4 PS1 PS3 PP1 PP3 PP4

Evidence Links 5

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
The 2740G>A G914R missense variant in the PIK3CA gene is previously reported in the literature and has been classified as PATHOGENIC. This variant has been confirmed de novo and has been shown to be consistent with a post-zygotic event (PMID: 22729224)(PS2_Strong). This variant has been identified in 5 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), and in 4 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 22729224), and it was identified in 2 tumor samples in COSMIC (PMID: 22729224, PMID: 28151489, PMID: 28502725, PMID: 30231930, COSMIC) (PS4 Met_Strong). This variant is located in the kinase domain (PM1). This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). This gene has a low rate of benign missense changes (PP2).
Met criteria codes
PM1_Supporting
located in a kinase domain
PM2
absent from gnomAD and ExAC
PS2
102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341 PubMed:22729224
PS4
also present in 2 tumor samples in COSMIC Upgraded to very strong
LR09-006 MCAP, LR11-070 had megalencephaly,vascular malformation,connective tissue dysplasia, ventriculomegaly and cerebellar tonsillar ectopia, LR06-341 had overgrowth, vasulcar malformation, connective tissued dyspalsia, and polymicrogyria PubMed:22729224
macrocephaly and right lateralized overgrowth, reported from birth, Magnetic Resonance Imaging that revealed ventriculomegaly, cerebellar tonsillar ectopia, a markedly thick corpus callosum, and white matter abnormalities PubMed:30231930
two patients both with phenotypic features consistent with MCAP 23.2% blood, 28.8% blood PubMed:28502725
P2376: isolated leg overgrowth (15.3% mutant allele fraction in skin); P1986: Cloves 8.2% skin 7.1% blood, P2739: Cloves (19.2% skin 0.0 blood) PubMed:28151489
PP2
PIK3CA meets the ExAC constraint z-score of >3.09
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
increased PIP3 levels in cell lines derived from patient lines showed PubMed:22729224
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as 3 small (<2 cm) meningiomas Analysis of blood revealed a mosaic PIK3CA c.2740G>A (p.Gly914Arg) and analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p.Arg262Ter) and loss of a portion of 22q, including NF2, SMARCB1, and LZTR1 genes. PubMed:28737257
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341 PubMed:22729224
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
increased PIP3 levels in cell lines derived from patient lines showed PubMed:22729224
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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