rs587777790

Positions:

• chr3-179199690-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.353G>A​(p.Gly118Asp) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 9.60

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CA. . Gene score misZ 5.5986 (greater than the threshold 3.09). Trascript score misZ 6.1406 (greater than threshold 3.09). GenCC has associacion of gene with 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 3-179199690-G-A is Pathogenic according to our data. Variant chr3-179199690-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 156446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179199690-G-A is described in Lovd as [Pathogenic]. Variant chr3-179199690-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.353G>A	p.Gly118Asp	missense_variant, splice_region_variant	3/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.353G>A	p.Gly118Asp	missense_variant, splice_region_variant	3/21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.353G>A	p.Gly118Asp	missense_variant, splice_region_variant	3/21	2	NM_006218.4	ENSP00000263967	P1
PIK3CA	ENST00000643187.1	c.353G>A	p.Gly118Asp	missense_variant, splice_region_variant	3/22			ENSP00000493507
PIK3CA	ENST00000675467.1	n.3160G>A		splice_region_variant, non_coding_transcript_exon_variant	2/20
PIK3CA	ENST00000675786.1	c.353G>A	p.Gly118Asp	missense_variant, splice_region_variant, NMD_transcript_variant	3/21			ENSP00000502323

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Angioosteohypertrophic syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Institute of Tissue Medicine and Pathology, University of Bern	Mar 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Feb 22, 2021	This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 28151489, PMID: 23246288, PMID: 26637981). PIK3CA variants associated with PROS, including this patient's alteration, overlap those reported as oncogenic variants found in multiple tumor types (cBioPortal and NCI's Genomic Data Commons cancer databases). This variant replaces the glycine at position 118 with aspartic acid within the linker region of the PIK3CA protein (UniProt P42336). Experimental studies have demonstrated that the p.Gly118Asp variant results in overactivation of the PI3K/AKT/mTOR pathway (PMID: 23246288). -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Keratoacanthoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Jun 07, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2021

- -

Cowden syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 10, 2013

- -

Cowden syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 07, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 118 of the PIK3CA protein (p.Gly118Asp). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 22949682, 23246288). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 156446). This missense change has been observed in individuals with PIK3CA-related overgrowth spectrum (PMID: 23246288, 28151489). -

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

-

This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PROS), which includes CLOVES syndrome (PMID: 23246288, PMID: 26637981, PMID: 28151489). PIK3CA variants associated with PROS, including this patient's alteration, overlap those reported as oncogenic variants found in multiple tumor types (cBioPortal and NCI's Genomic Data Commons cancer databases). This variant replaces the glycine at position 118 with aspartic acid within the linker region of the PIK3CA protein (UniProt P42336). Experimental studies have demonstrated that the p.Gly118Asp variant results in overactivation of the PI3K/AKT/mTOR pathway (PMID: 23246288). -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Thyroid tumor Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.017	D;.
Sift4G	Uncertain	0.018	D;.
Polyphen		0.99	D;.
Vest4		0.98
MutPred		0.50		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.80
MPC		1.8
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.17		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: rs587777790; hg19: chr3-178917478; COSMIC: COSV55877290; COSMIC: COSV55877290;