rs121913284

chr3-179203765-T-Achr3-179203765-T-Cchr3-179203765-T-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_006218.4(PIK3CA):c.1035T>A(p.Asn345Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N345H) 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:14
• Conservation: PhyloP100: 1.96

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 Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_006218.4 (PIK3CA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376051
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr3-179203764-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2580765.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• PP5: Variant 3-179203765-T-A is Pathogenic according to our data. Variant chr3-179203765-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 376050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1035T>A	p.Asn345Lys	missense_variant	5/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1035T>A	p.Asn345Lys	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1035T>A	p.Asn345Lys	missense_variant	5/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Seborrheic keratosis;C0024623:Gastric cancer;C0242379:Lung cancer;C0265552:Congenital macrodactylia;C0334082:Epidermal nevus;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0919267:Neoplasm of ovary;C1865285:Megalencephaly-capillary malformation-polymicrogyria syndrome;C2239176:Hepatocellular carcinoma;C2751313:CLAPO syndrome;C2752042:CLOVES syndrome;C3554518:Cowden syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2020

- -

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Oct 27, 2023

The PIK3CA c.1035T>A (p.Asn345Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in at least three individuals affected with PROS disorders (Parker VER et al., PMID: 30270358, Tian W et al., PMID: 35122151; McNulty SN et al., PMID: 31585106). The PIK3CA c.1035T>A (p.Asn345Lys) variant has been reported in numerous cases in the cancer database COSMIC (COSMIC Genomic Mutation ID COSV55873276 ) and it has been reported in the ClinVar database as pathogenic by two submitters (ClinVar ID: 376050). This variant is absent from the general population (gnomAD V.3.1.2), indicating it is not a common variant. The PIK3CA c.1035T>A (p.Asn345Lys) variant is considered to be a strong oncogenic variant (Gymnopoulos M et al., PMID: 17376864) and resides in the C2 catalytic subunit of PIK3CA that is defined as a critical functional domain (Madsen R et al., PMID: 30197175; Keppler-Noreuil KM et al., PMID: 25557259). Functional in vitro studies show that this variant leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling, indicating that this variant impacts protein function (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene 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 (Lai A 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 PIK3CA c.1035T>A (p.Asn345Lys) variant is classified as pathogenic. -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Abnormal cardiovascular system morphology Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

Adenoid cystic carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.50
Sift	Benign	0.34	T;.
Sift4G	Benign	0.25	T;.
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.60		Gain of methylation at N345 (P = 0.0142);Gain of methylation at N345 (P = 0.0142);
MVP		0.78
MPC		2.0
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.75
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: rs121913284; hg19: chr3-178921553; COSMIC: COSV55873276; COSMIC: COSV55873276;