3-179234285-T-C
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3
The NM_006218.4(PIK3CA):c.3128T>C(p.Met1043Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1043I) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
PIK3CA
NM_006218.4 missense
NM_006218.4 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 7.59
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a domain PI3K/PI4K catalytic (size 286) in uniprot entity PK3CA_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_006218.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-179234286-G-T is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the PIK3CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 5.5986 (above the threshold of 3.09). Trascript score misZ: 6.1406 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary breast carcinoma, vascular malformation, Cowden disease, Cowden syndrome 5, CLOVES syndrome, familial ovarian cancer, megalencephaly-capillary malformation-polymicrogyria syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.809
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:11
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Glioblastoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Malignant neoplasm of body of uterus Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Gastric adenocarcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Pancreatic adenocarcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Breast neoplasm Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Neoplasm of brain Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Transitional cell carcinoma of the bladder Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Adenoid cystic carcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Thyroid tumor Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Neoplasm of the large intestine Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Squamous cell carcinoma of the head and neck Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of disorder (P = 0.0936);
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