rs1057519926

Positions:

• chr3-179210293-A-C
• chr3-179210293-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PM5 PP2

The NM_006218.4(PIK3CA):​c.1359A>C​(p.Glu453Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E453Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48

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 Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_006218.4 (PIK3CA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376472
• PM1: In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 36 pathogenic changes around while only 2 benign (95%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-179210291-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 376470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PIK3CA

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1359A>C	p.Glu453Asp	missense_variant	8/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1359A>C	p.Glu453Asp	missense_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1359A>C	p.Glu453Asp	missense_variant	8/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.53	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.67	N;.
REVEL	Benign	0.28
Sift	Benign	0.34	T;.
Sift4G	Benign	0.43	T;.
Polyphen		0.0060	B;.
Vest4		0.68
MutPred		0.84		Loss of catalytic residue at G451 (P = 0.1666);Loss of catalytic residue at G451 (P = 0.1666);
MVP		0.87
MPC		0.73
ClinPred		0.49	T
GERP RS		4.5
Varity_R		0.61
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-178928081; COSMIC: COSV55944133;