rs397514565
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong
The NM_006218.4(PIK3CA):c.1133G>A(p.Cys378Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C378R) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PIK3CA
NM_006218.4 missense
NM_006218.4 missense
Scores
8
6
5
Clinical Significance
Conservation
PhyloP100: 9.50
Genes affected
PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
?
In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 35 pathogenic changes around while only 2 benign (95%) in NM_006218.4
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr3-179204575-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 917489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, PIK3CA
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.843
PP5
?
Variant 3-179204576-G-A is Pathogenic according to our data. Variant chr3-179204576-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3CA | NM_006218.4 | c.1133G>A | p.Cys378Tyr | missense_variant | 6/21 | ENST00000263967.4 | |
PIK3CA | XM_006713658.5 | c.1133G>A | p.Cys378Tyr | missense_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3CA | ENST00000263967.4 | c.1133G>A | p.Cys378Tyr | missense_variant | 6/21 | 2 | NM_006218.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1363934Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 684336
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1363934
Hom.:
Cov.:
21
AF XY:
AC XY:
0
AN XY:
684336
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 24, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 26637981). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039704). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024). A different missense change at the same codon (p.Cys378Arg) has been reported to be associated with PIK3CA related disorder (ClinVar ID: VCV000917489). The variant was detected at ~13% allele frequency, suggesting mosaic state. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Dec 20, 2018 | - - |
PIK3CA related overgrowth syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Dec 08, 2014 | - - |
Pathogenic, criteria provided, single submitter | research | Care4Rare-SOLVE, CHEO | - | - - |
PIK3CA-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 30, 2022 | The PIK3CA c.1133G>A variant is predicted to result in the amino acid substitution p.Cys378Tyr. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. - |
Cowden syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 39704). This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome (MCAP) and symptoms consistent with PIK3CA-related overgrowth syndrome (PMID: 22729224, 27631024, 28151489). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 378 of the PIK3CA protein (p.Cys378Tyr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Benign
T;.
Sift4G
Benign
T;.
Polyphen
P;.
Vest4
MutPred
Loss of catalytic residue at P377 (P = 0.0134);Loss of catalytic residue at P377 (P = 0.0134);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at