3-179218307-A-G

Variant names:

• chr3-179218307-A-G
• rs397517201
• NM_006218.4:c.1637A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1637A>G​(p.Gln546Arg) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q546P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 8.95
• Publications: 299 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 17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain 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 chr3-179218307-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.925
• PP5: Variant 3-179218307-A-G is Pathogenic according to our data. Variant chr3-179218307-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 45466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006218.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.1637A>G	p.Gln546Arg	missense	Exon 10 of 21	NP_006209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.1637A>G	p.Gln546Arg	missense	Exon 10 of 21	ENSP00000263967.3
	PIK3CA	ENST00000643187.1		c.1637A>G	p.Gln546Arg	missense	Exon 10 of 22	ENSP00000493507.1
	PIK3CA	ENST00000462255.2	TSL:3	n.99A>G		non_coding_transcript_exon	Exon 1 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ovarian neoplasm Pathogenic:2

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Aug 10, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIK3CA related overgrowth syndrome Pathogenic:1

Aug 09, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PIK3CA c.1637A>G (p.Gln546Arg) variant was identified at an allelic fraction consistent with somatic origin. The PIK3CA c.1637A>G (p.Gln546Arg) variant has been reported in multiple individuals affected with PROS disorders, including patients with lymphatic malformations (Kuentz P et al., PMID: 28151489; Piacitelli AM et al., PMID: 30063105; Parker VER et al., PMID: 30270358; McNulty SN et al., PMID: 31585106; Brouillard P et al., PMID: 34112235). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic by multiple submitters (ClinVar Variation ID: 54633). It has also been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55876869). The PIK3CA c.1637A>G (p.Gln546Arg) variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors suggest that this variant may have a deleterious impact on the structure and/or function of the PIK3CA-encoded protein. Functional studies show p.Gln546Arg to be activating, as demonstrated by increased transformation ability in multiple cell lines (Dogruluk T et al., PMID: 26627007; Ng PK et al., PMID: 29533785). Multiple variants in the same codon, p.Gln546Glu, p.Gln546His, p.Gln546Leu, p.Gln546Lys, and p.Gln546Pro, have been reported and are considered pathogenic (ClinVar Variation IDs: 13654, 376491, 375899, 13657, 375898). 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.1637A>G (p.Gln546Arg) 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

not provided Pathogenic:1

Feb 04, 2021

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: 25681199, PMID: 31585106). Phenotypic information was limited in the majority of cases, but one individual had a clinical diagnosis of Fibro-Adipose Vascular Anomaly (FAVA) (PMID: 25681199). 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.Gln546Arg replaces the glutamine at codon 546 with arginine within the helical domain of the PIK3CA protein (UniProt P42336). Experimental studies have demonstrated that the p.Gln546Arg variant causes overactivation of the PI3K/AKT/mTOR pathway and increased proliferation in vitro (PMID: 26627007).

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.65
Sift	Benign	0.11	T
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.89
MutPred		0.83		Loss of ubiquitination at K548 (P = 0.0982)
MVP		0.91
MPC		2.8
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.67
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397517201; hg19: chr3-178936095; COSMIC: COSV55876869; COSMIC: COSV55876869;