rs1057519929

Variant names:

• chr3-179199066-G-A
• rs1057519929
• NM_006218.4:c.241G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-179199066-G-A
• chr3-179199066-G-C
• chr3-179199066-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.241G>A​(p.Glu81Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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:7 O:1
• Conservation: PhyloP100: 6.36
• Publications: 122 publications found

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]

PIK3CA Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• vascular malformation

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 5

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a domain PI3K-ABD (size 89) in uniprot entity PK3CA_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) 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 megalencephaly-capillary malformation-polymicrogyria syndrome, vascular malformation, Cowden syndrome 5, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, Cowden disease, hereditary breast carcinoma, familial ovarian cancer.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 3-179199066-G-A is Pathogenic according to our data. Variant chr3-179199066-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 376478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.241G>A	p.Glu81Lys	missense_variant	Exon 2 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.241G>A	p.Glu81Lys	missense_variant	Exon 2 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.241G>A	p.Glu81Lys	missense_variant	Exon 2 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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 29, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31585106, PMID: 22729224, PMID: 25915946). 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). The p.Glu81Lys replaces the glycine at codon 81 with lysine within the PI3K adaptor-binding domain of the protein (UniProt P42336). Experimental studies have demonstrated that the p.Glu81Lys variant causes overactivation of the PI3K/AKT/mTOR pathway (PMID: 25915946). -

Jun 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28502730, 34758253, 25915946, 26619011, 23592320, 29549527, 27798902, 21531001, 29493003, 33539671, 34969754, 34779417, 32923889, 24037760, 33503190, 33442366, 30243889, 33105631, 32235312, 22729224, 29575851, 29643510, 34684076, 34736091, 34150029) -

PIK3CA related overgrowth syndrome Pathogenic:1

Sep 20, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.241G>A (p.Glu81Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected by PROS disorders (Rivière JB et al., PMID: 22729224; Loconte DC et al., PMID: 25915946; Kuentz P et al., PMID: 28151489; Leiter SM et al., PMID: 28566443; Zhang M et al., PMID: 30996962; Mirzaa GM et al., PMID: 23592320; Denorme P et al., PMID: 29493003; Paolacci S et al., PMID: 33105631; Ranieri C et al., PMID: 29549527). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic by multiple submitters in both a somatic and germline state (ClinVar ID: 376478) and in multiple cases in the cancer database COSMIC (ID: COSV55873676). This variant is absent from the general population database (gnomAD v.3.1.2), indicating that it is not a common variant. This variant resides within a p85-binding domain, amino acids 32-107, of PIK3CA that is defined as a critical functional domain (Burke JE et al., PMID: 22949682; Zhang M et al., PMID: 30996962). Functional in vitro studies show that this variant induces Akt-mTOR signaling and enhanced cell growth, indicating that this variant impacts protein function (Jin N et al., PMID: 34779417; Loconte DC et al., PMID: 25915946). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. The PIK3CA gene is defined by ClinGen's Brain Malformation expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Lai et al., PMID: 35997716). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.241G>A (p.Glu81Lys) variant is classified as pathogenic. -

Abnormal cardiovascular system morphology Pathogenic:1

-

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Cowden syndrome Pathogenic:1

Dec 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CA protein function. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 81 of the PIK3CA protein (p.Glu81Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PIK3CA-related overgrowth spectrum (PMID: 22729224, 25915946). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376478). For these reasons, this variant has been classified as Pathogenic. -

CLOVES syndrome Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	2.9	M;.;.
PhyloP100		6.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.91
MutPred		0.70		Gain of methylation at E81 (P = 0.0034);Gain of methylation at E81 (P = 0.0034);Gain of methylation at E81 (P = 0.0034);
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.89
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1057519929; hg19: chr3-178916854; COSMIC: COSV55873676; COSMIC: COSV55873676;