NM_006218.4:c.341A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4BS2

The NM_006218.4(PIK3CA):c.341A>G(p.Asn114Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,570,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N114Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.94

Publications

4 publications found

Variant links:

COSMIC-nc: COSV55978536

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 Submitted by: ClinGen
megalencephaly-capillary malformation-polymicrogyria syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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)
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PIK3CA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_006218.4

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 megalencephaly-capillary malformation-polymicrogyria syndrome, vascular malformation, Cowden syndrome 5, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, Cowden disease, hereditary breast carcinoma, familial ovarian cancer.

BP4

Computational evidence support a benign effect (MetaRNN=0.3424412).

BS2

High AC in GnomAdExome4 at 24 AD gene.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.341A>G	p.Asn114Ser	missense	Exon 2 of 21	NP_006209.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.341A>G	p.Asn114Ser	missense	Exon 2 of 21	ENSP00000263967.3
PIK3CA	ENST00000955190.1		c.341A>G	p.Asn114Ser	missense	Exon 2 of 21	ENSP00000625249.1
PIK3CA	ENST00000876545.1		c.341A>G	p.Asn114Ser	missense	Exon 3 of 22	ENSP00000546604.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000191

AC:

AN:

209422

AF XY:

0.0000264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000124

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000200

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000169

AC:

AN:

1417992

Hom.:

Cov.:

AF XY:

0.0000241

AC XY:

AN XY:

704456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31252

American (AMR)

AF:

0.00

AC:

AN:

35118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23586

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.0000382

AC:

AN:

78538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51896

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.0000174

AC:

AN:

1094188

Other (OTH)

AF:

0.0000171

AC:

AN:

58396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41592

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000728

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000248

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cowden syndrome (1)

not provided (1)

Seborrheic keratosis;C0024623:Gastric cancer;C0242379:Lung cancer;C0265552:Congenital macrodactylia;C0334082:Epidermal nevus;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C1140680:Ovarian cancer;C1847521:Hemifacial myohyperplasia;C1865285:Megalencephaly-capillary malformation-polymicrogyria syndrome;C2239176:Hepatocellular carcinoma;C2751313:CLAPO syndrome;C2752042:CLOVES syndrome;C3554518:Cowden syndrome 5;C5561991:Cerebral cavernous malformation 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.053

MetaRNN

Benign

0.34

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.9

PhyloP100

8.9

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.34

Sift

Benign

0.10

Sift4G

Benign

0.14

Polyphen

0.98

Vest4

0.53

MutPred

0.47

Gain of phosphorylation at N114 (P = 0.0501)

MVP

0.80

MPC

0.63

ClinPred

0.34

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.75

Mutation Taster

=54/46

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over