rs397517201

Positions:

• chr3-179218307-A-C
• chr3-179218307-A-G
• chr3-179218307-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_006218.4(PIK3CA):​c.1637A>C​(p.Gln546Pro) 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, single submitter P:2
• 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 11 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, 0.921
• PP5: Variant 3-179218307-A-C is Pathogenic according to our data. Variant chr3-179218307-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 375898.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1637A>C	p.Gln546Pro	missense_variant	10/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1637A>C	p.Gln546Pro	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>C	p.Gln546Pro	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:2

Revision: criteria provided, single submitter

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

-

Variants occurring at p.Gln546 have previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth spectrum disorder and individuals with cancer (PMID: 25681199, PMID: 29985963, PMID: 37624421, COSV55875400). The p.Gln546Pro variant substitutes the glutamine at position 546 with proline within the PIK helical domain of the PIK3CA protein (UniProt P42336). This and other variants at p.Gln546 have been shown to be activating variants that result in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 17376864, PMID: 26627007). -

Ovarian neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.73
Sift	Benign	0.067	T;.
Sift4G	Benign	0.21	T;.
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.79		Loss of ubiquitination at K548 (P = 0.0699);Loss of ubiquitination at K548 (P = 0.0699);
MVP		0.89
MPC		3.0
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.90

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: COSV55875400; COSMIC: COSV55875400;