rs121913284

Variant names:

• chr3-179203765-T-A
• rs121913284
• NM_006218.4:c.1035T>A

Your query was ambiguous. Multiple possible variants found:

• chr3-179203765-T-A
• chr3-179203765-T-C
• chr3-179203765-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• 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 13 ACMG points.

• PM1: In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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 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.
• 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 rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1035T>A	p.Asn345Lys	missense_variant	Exon 5 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1035T>A	p.Asn345Lys	missense_variant	Exon 5 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1035T>A	p.Asn345Lys	missense_variant	Exon 5 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Oct 27, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:1

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormal cardiovascular system morphology Pathogenic:1

-

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

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

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

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	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;.
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;