rs200001957

Variant names:

• chr3-179199807-A-G
• rs200001957
• NM_006218.4:c.470A>G
• PIK3CA p.Asn157Ser

Your query was ambiguous. Multiple possible variants found:

• chr3-179199807-A-G
• chr3-179199807-A-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO8_SupportingB3_Supporting

The NM_006218.4(PIK3CA):c.470A>G (p.Asn157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene PIK3CA is a known oncogene (CancerMine: 3 TSG, 156 oncogene, 103 driver citations). The gene PIK3CA is a cancer driver gene (CancerMine: 3 TSG, 156 oncogene, 103 driver citations). The variant allele was found at a cumulative frequency of 0.000018 (AC=29) in the gnomAD database across 1,612,774 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000013. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N157D: Uncertain_significance (ClinVar VariationId 4861898, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86
• Publications: 1 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, STRONG Submitted by: G2P, PanelApp Australia
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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)
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for PIK3CA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000013 — very rare (O3 supporting [+1])
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 6.15 (threshold ≥3.09 for constraint)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PIK3CA NM_006218.4	MANE Select	c.470A>G p.Asn157Ser	missense	Exon 3 of 21	Prot: NP_006209.2 UniProt:

PIK3CA NM_006218.4

MANE Select

HGVSc / HGVSpc.470A>Gp.Asn157Ser

Exon rankExon 3 of 21

missense

Prot: NP_006209.2UniProt: P42336

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PIK3CA ENST00000263967.4	TSL:2MANE Select	c.470A>G p.Asn157Ser	missense	Exon 3 of 21	Prot: ENSP00000263967.3 UniProt:
	PIK3CA ENST00000955190.1		c.470A>G p.Asn157Ser	missense	Exon 3 of 21	Prot: ENSP00000625249.1 UniProt:
	PIK3CA ENST00000876545.1		c.470A>G p.Asn157Ser	missense	Exon 4 of 22	Prot: ENSP00000546604.1 UniProt:

PIK3CA ENST00000263967.4

TSL:2MANE Select

HGVSc / HGVSpc.470A>Gp.Asn157Ser

Exon rankExon 3 of 21

missense

Prot: ENSP00000263967.3UniProt: P42336

PIK3CA ENST00000955190.1

HGVSc / HGVSpc.470A>Gp.Asn157Ser

Exon rankExon 3 of 21

missense

Prot: ENSP00000625249.1UniProt: A0ACI8UU87

PIK3CA ENST00000876545.1

HGVSc / HGVSpc.470A>Gp.Asn157Ser

Exon rankExon 4 of 22

missense

Prot: ENSP00000546604.1UniProt: P42336

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152172	Cov:32
GnomAD2 exomes	AF: 0.0000120	AC:3	Hom:	AN:249476	Cov:
GnomAD4 exome	AF: 0.0000171	AC:25	Hom:0	AN:1460602	Cov:30
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152172	Cov:32
TOPMed (Bravo)	AF: 0.0000340	AC:9	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000246	AC:	Hom:	AN:	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28414	0.0000347	1	28830
Epi25(Epilepsy)	0.0000715	3	41952	0.0000150	1	66882
SCHEMA(Schizophrenia)	0.0000530	6	113110	0.0000210	4	190590

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cowden syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.083
FATHMM_MKL	Benign	0.63	D
FuncVEP CTI	Benign	0.0039
GPN-Star LLR	N/A	-6.7
GPN-Star score	N/A	6.7
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.85	T
Mutation Taster	N/A	88/12	polymorphism
MutationAssessor	Benign	0.14	N
PhyloP100	Benign	2.9
popEVE	Benign	-3.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.11	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.093
Sift	Benign	0.74	T
Sift4G	Benign	0.73	T
Varity_R	N/A	0.10
VESM-3B	Benign	-3.2

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200001957;

hg19: chr3-178917595;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar