rs371049193

chr3-179225998-G-Achr3-179225998-G-Cchr3-179225998-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_006218.4(PIK3CA):c.2453G>A(p.Arg818His) variant causes a missense change. The variant allele was found at a frequency of 0.0000208 in 1,444,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain PI3K/PI4K catalytic (size 286) in uniprot entity PK3CA_HUMAN there are 38 pathogenic changes around while only 1 benign (97%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.2453G>A	p.Arg818His	missense_variant	17/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.2453G>A	p.Arg818His	missense_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.2453G>A	p.Arg818His	missense_variant	17/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247624 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134360

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000208 AC: 30 AN: 1444656 Hom.: 0 Cov.: 25 AF XY: 0.0000222 AC XY: 16 AN XY: 719462

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000219

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cowden syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 456540). This variant has not been reported in the literature in individuals affected with PIK3CA-related conditions. This variant is present in population databases (rs371049193, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 818 of the PIK3CA protein (p.Arg818His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.019	D;.
Polyphen		0.22	B;.
Vest4		0.50
MVP		0.91
MPC		2.7
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371049193; hg19: chr3-178943786; COSMIC: COSV55912779;