chr3-179199807-A-T

Variant names:

• chr3-179199807-A-T
• rs200001957
• NM_006218.4:c.470A>T
• PIK3CA p.Asn157Ile

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 (ACMG Germline Pathogenicity v2019). PM2PP2BP4_Moderate

The NM_006218.4(PIK3CA):c.470A>T (p.Asn157Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N157D: Uncertain_significance (ClinVar VariationId 4861898, 1 star); p.N157S: Uncertain_significance (ClinVar VariationId 580643, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

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
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 6.149). ClinVar shows strong pathogenic missense enrichment: 99 P/LP and 14 B/LB missense entries (ratio 7.1×).
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>T p.Asn157Ile	missense	Exon 3 of 21	Prot: NP_006209.2 UniProt:

PIK3CA NM_006218.4

MANE Select

HGVSc / HGVSpc.470A>Tp.Asn157Ile

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>T p.Asn157Ile	missense	Exon 3 of 21	Prot: ENSP00000263967.3 UniProt:
	PIK3CA ENST00000955190.1		c.470A>T p.Asn157Ile	missense	Exon 3 of 21	Prot: ENSP00000625249.1 UniProt:
	PIK3CA ENST00000876545.1		c.470A>T p.Asn157Ile	missense	Exon 4 of 22	Prot: ENSP00000546604.1 UniProt:

PIK3CA ENST00000263967.4

TSL:2MANE Select

HGVSc / HGVSpc.470A>Tp.Asn157Ile

Exon rankExon 3 of 21

missense

Prot: ENSP00000263967.3UniProt: P42336

PIK3CA ENST00000955190.1

HGVSc / HGVSpc.470A>Tp.Asn157Ile

Exon rankExon 3 of 21

missense

Prot: ENSP00000625249.1UniProt: A0ACI8UU87

PIK3CA ENST00000876545.1

HGVSc / HGVSpc.470A>Tp.Asn157Ile

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.70	D
FuncVEP CTI	Benign	0.032
GPN-Star LLR	N/A	-9.6
GPN-Star score	N/A	9.6
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.85	T
Mutation Taster	N/A	77/23	polymorphism
MutationAssessor	Benign	0.69	N
PhyloP100	Benign	2.9
popEVE	Benign	-3.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.17
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Varity_R	N/A	0.37
VESM-3B	Benign	-5.6

Showing 28 of 28 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