3-179234286-G-T

Variant names:

• chr3-179234286-G-T
• rs121913283
• NM_006218.4:c.3129G>T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.3129G>T​(p.Met1043Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 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
• 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.
• PP5: Variant 3-179234286-G-T is Pathogenic according to our data. Variant chr3-179234286-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 217292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179234286-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.3129G>T	p.Met1043Ile	missense_variant	Exon 21 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.3129G>T	p.Met1043Ile	missense_variant	Exon 21 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.3129G>T	p.Met1043Ile	missense_variant	Exon 21 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:2

-

Care4Rare-SOLVE, CHEO

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 18, 2014

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo variant with confirmed parentage in multiple patients with PIK3CA-related overgrowth and brain malformations spectrum disorder in the published literature (Riviere et al., 2012; Mirzaa et al., 2016) and mosaic variant in a patient with PIK3CA-related overgrowth and brain malformations spectrum disorder referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29883676, 26627007, 18628094, 18516290, 27631024, 33745098, 29707142, 29650325, 29453417, 22729224, 25157968, 15930273, 34693559, 22120714, 35468270, 36635288, 37456262, 36468132, Nasomyont[CaseReport], 36710374, 32398863, 35070505, 34638442, 35715244, 35359373, 35154272) -

Cowden syndrome Pathogenic:1

Jul 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 1043 of the PIK3CA protein (p.Met1043Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant has been reported to be de novo in an individual affected with megalencephaly-capillary malformation syndrome (PMID: 22729224). ClinVar contains an entry for this variant (Variation ID: 217292). Experimental studies have shown that this missense change increases PIK3CA basal kinase activity and lipid binding (PMID: 15930273, 22120714). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.3	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.016	D
Sift4G	Benign	0.11	T
Polyphen		0.14	B
Vest4		0.84
MutPred		0.54		Loss of ubiquitination at K1041 (P = 0.0502);
MVP		0.98
MPC		1.6
ClinPred		0.92	D
GERP RS		6.1
Varity_R		0.60
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913283; hg19: chr3-178952074; COSMIC: COSV55878974; COSMIC: COSV55878974;