3-179218307-A-G

Position:

• chr3-179218307-A-G

Variant summary

Our verdict is Pathogenic. Variant got 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. Q546H) has been classified as 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

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain PIK helical (size 177) in uniprot entity PK3CA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr3-179218308-G-T is described in Lovd as [Pathogenic].
• 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: 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 id is 45466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1637A>G	p.Gln546Arg	missense_variant	10/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1637A>G	p.Gln546Arg	missense_variant	10/21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1637A>G	p.Gln546Arg	missense_variant	10/21	2	NM_006218.4	ENSP00000263967.3

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

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2010	- -
Likely pathogenic, no assertion criteria provided	research	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Dec 01, 2018	- -

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Aug 09, 2023

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 04, 2021

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). -

Abnormal cardiovascular system morphology Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.5	M;.
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);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

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