Genetic Variant PIK3CA:c.-77+17C>T (chr3-179148620-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006218.4(PIK3CA):c.-77+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,296 control chromosomes in the GnomAD database, including 2,841 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2825 hom., cov: 32)

Exomes 𝑓: 0.25 ( 16 hom. )

Consequence

PIK3CA
NM_006218.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.886

Publications

36 publications found

Variant links:

COSMIC-nc: COSV55874885

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4 link	c.-77+17C>T		intron_variant	Intron 1 of 20	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.-77+401C>T		intron_variant	Intron 1 of 20		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIK3CA	ENST00000263967.4 link	c.-77+17C>T	intron_variant	Intron 1 of 20	2	NM_006218.4	ENSP00000263967.3	P42336
PIK3CA	ENST00000643187.1 link	c.-77+17C>T	intron_variant	Intron 1 of 21			ENSP00000493507.1	A0A2R8Y2F6
PIK3CA	ENST00000477735.1 link	c.-77+401C>T	intron_variant	Intron 1 of 1	4		ENSP00000418145.1	C9J951

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26634

AN:

151804

Hom.:

2822

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0644

Gnomad AMI

AF:

0.315

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.0671

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.141

Gnomad NFE

AF:

0.246

Gnomad OTH

AF:

0.170

GnomAD4 exome

AF:

0.250

AC:

AN:

376

Hom.:

Cov.:

AF XY:

0.248

AC XY:

AN XY:

262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.200

AC:

AN:

European-Finnish (FIN)

AF:

0.417

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.258

AC:

AN:

314

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.175

AC:

26644

AN:

151920

Hom.:

2825

Cov.:

AF XY:

0.172

AC XY:

12786

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0646

AC:

2680

AN:

41514

American (AMR)

AF:

0.160

AC:

2448

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

753

AN:

3460

East Asian (EAS)

AF:

0.0672

AC:

346

AN:

5146

South Asian (SAS)

AF:

0.168

AC:

812

AN:

4826

European-Finnish (FIN)

AF:

0.209

AC:

2208

AN:

10546

Middle Eastern (MID)

AF:

0.134

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.246

AC:

16711

AN:

67862

Other (OTH)

AF:

0.172

AC:

362

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1094

2188

3283

4377

5471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.209

Hom.:

601

Bravo

AF:

0.166

Asia WGS

AF:

0.112

AC:

388

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

-0.89

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over