rs2230461

chr3-179209622-A-Gchr3-179209622-A-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_006218.4(PIK3CA):c.1173A>G(p.Ile391Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0661 in 1,609,518 control chromosomes in the GnomAD database, including 4,921 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I391V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (1192 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3729 hom.)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Benign reviewed by expert panel B:8 O:1
• Conservation: PhyloP100: 1.33

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 Benign. Variant got -17 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
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018924475).
• BP6: Variant 3-179209622-A-G is Benign according to our data. Variant chr3-179209622-A-G is described in ClinVar as [Benign]. Clinvar id is 135038.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-179209622-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1173A>G	p.Ile391Met	missense_variant	7/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1173A>G	p.Ile391Met	missense_variant	7/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1173A>G	p.Ile391Met	missense_variant	7/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15273 AN: 151982 Hom.: 1188 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0769

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0636

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0621 AC: 15419 AN: 248260 Hom.: 792 AF XY: 0.0593 AC XY: 7988 AN XY: 134692

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0528

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0193

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0826

GnomAD4 exome AF: 0.0625 AC: 91077 AN: 1457418 Hom.: 3729 Cov.: 29 AF XY: 0.0611 AC XY: 44326 AN XY: 725112

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.0571

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.0626

Gnomad4 OTH exome AF: 0.0775

GnomAD4 genome AF: 0.100 AC: 15283 AN: 152100 Hom.: 1192 Cov.: 32 AF XY: 0.0957 AC XY: 7117 AN XY: 74374

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.0769

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.0636

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0759 Hom.: 789

Bravo AF: 0.113

TwinsUK AF: 0.0585 AC: 217

ALSPAC AF: 0.0519 AC: 200

ESP6500AA AF: 0.201 AC: 751

ESP6500EA AF: 0.0680 AC: 558

ExAC AF: 0.0649 AC: 7839

Asia WGS AF: 0.0230 AC: 82 AN: 3478

EpiCase AF: 0.0778

EpiControl AF: 0.0812

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Benign:1

Benign, reviewed by expert panel

curation

ClinGen Brain Malformations Variant Curation Expert Panel

Feb 11, 2022

The c.1173A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Ile391Met). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.2113 in African/African American population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). This variant was identified the homozygous state in >3 individuals within control databases (BS2). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM1_P, BA1, BS2, PP2; -10 points (VCEP specifications version 1; Approved: 1/31/2021) -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Cowden syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Cowden syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	16
Dann	Benign	0.93
DEOGEN2	Uncertain	0.76	D;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.0018	P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.24
Sift	Benign	0.15	T;.
Sift4G	Benign	0.10	T;.
Polyphen		0.011	B;.
Vest4		0.096
MPC		0.83
ClinPred		0.0076	T
GERP RS		-0.00076
Varity_R		0.31
gMVP		0.61

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: rs2230461; hg19: chr3-178927410; COSMIC: COSV55885079;