rs115746478

chr3-179199700-C-Gchr3-179199700-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_006218.4(PIK3CA):c.363C>G(p.Ile121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I121L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.73

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• BP4: Computational evidence support a benign effect (MetaRNN=0.42082593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.363C>G	p.Ile121Met	missense_variant	3/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.363C>G	p.Ile121Met	missense_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.363C>G	p.Ile121Met	missense_variant	3/21	2	NM_006218.4	P1
PIK3CA	ENST00000643187.1	c.363C>G	p.Ile121Met	missense_variant	3/22
PIK3CA	ENST00000675467.1	n.3170C>G		non_coding_transcript_exon_variant	2/20
PIK3CA	ENST00000675786.1	c.363C>G	p.Ile121Met	missense_variant, NMD_transcript_variant	3/21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	6.8
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.50		Loss of catalytic residue at I121 (P = 0.0367);Loss of catalytic residue at I121 (P = 0.0367);
MVP		0.65
MPC		1.8
ClinPred		0.97	D
GERP RS		-12
Varity_R		0.82
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-178917488; COSMIC: COSV99081706; COSMIC: COSV99081706;