rs1553820490

Positions:

• chr3-179199723-A-G
• chr3-179199723-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006218.4(PIK3CA):​c.386A>G​(p.Asp129Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CA. . Gene score misZ 5.5986 (greater than the threshold 3.09). Trascript score misZ 6.1406 (greater than threshold 3.09). GenCC has associacion of gene with hereditary breast carcinoma, vascular malformation, Cowden disease, Cowden syndrome 5, CLOVES syndrome, familial ovarian cancer, megalencephaly-capillary malformation-polymicrogyria syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.386A>G	p.Asp129Gly	missense_variant	3/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.386A>G	p.Asp129Gly	missense_variant	3/21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.386A>G	p.Asp129Gly	missense_variant	3/21	2	NM_006218.4	ENSP00000263967.3
PIK3CA	ENST00000643187.1	c.386A>G	p.Asp129Gly	missense_variant	3/22			ENSP00000493507.1
PIK3CA	ENST00000675467.1	n.3193A>G		non_coding_transcript_exon_variant	2/20
PIK3CA	ENST00000675786.1	n.386A>G		non_coding_transcript_exon_variant	3/21			ENSP00000502323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2021

The p.D129G variant (also known as c.386A>G), located in coding exon 2 of the PIK3CA gene, results from an A to G substitution at nucleotide position 386. The aspartic acid at codon 129 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cowden syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2017

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with PIK3CA-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 129 of the PIK3CA protein (p.Asp129Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Uncertain	0.39
Sift	Benign	0.039	D;.
Sift4G	Benign	0.11	T;.
Polyphen		0.0020	B;.
Vest4		0.91
MutPred		0.51		Loss of stability (P = 0.0496);Loss of stability (P = 0.0496);
MVP		0.87
MPC		1.0
ClinPred		0.95	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.81

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: rs1553820490; hg19: chr3-178917511;