rs1057519942

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong

The NM_006218.4(PIK3CA):c.1030G>A(p.Val344Met) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V344G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.45

Publications

67 publications found

Variant links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr3-179203761-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376497.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the PIK3CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 5.5986 (above the threshold of 3.09). Trascript score misZ: 6.1406 (above the threshold of 3.09). GenCC associations: The gene is linked to megalencephaly-capillary malformation-polymicrogyria syndrome, vascular malformation, Cowden syndrome 5, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, Cowden disease, hereditary breast carcinoma, familial ovarian cancer.

PP5

Variant 3-179203760-G-A is Pathogenic according to our data. Variant chr3-179203760-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 376498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4 link	c.1030G>A	p.Val344Met	missense_variant	Exon 5 of 21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.1030G>A	p.Val344Met	missense_variant	Exon 5 of 21		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 link	c.1030G>A	p.Val344Met	missense_variant	Exon 5 of 21	2	NM_006218.4	ENSP00000263967.3		P42336

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cowden syndrome 5

Pathogenic:3

Nov 07, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 25, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

May 20, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21984976, 26226847, 31278258, 26492180, 34906519, 26619011, 24573554, 22653804, 25343854, 22102435, 23907151, 27631024, 30167082, 28973083, 29296277, 31568861, 31785789, 35599849) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIK3CA: PS2, PM2, PS4:Moderate, PP3, PP4 -

PIK3CA related overgrowth syndrome

Pathogenic:1

May 23, 2021

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PIK3CA c.1030G>A p.(Val344Met) variant is a missense variant that has been reported in a heterozygous state in three individuals with features of megalencephaly-capillary malformation; the variant was maternally inherited in one individual and occurred de novo in the other two cases (Mirzaa et al. 2016; Yeung et al. 2017; De Graer et al. 2020). Meng et al. (2017) also reported the variant in a heterozygous state in a critically ill infant for whom no additional phenotype details were provided. This variant is not observed in version 2.1.1 or 3.1.2 of the Genome Aggregation Database. Based on the collective evidence the c.1030G>A p.(Val344Met) variant is classified as pathogenic for PIK3CA-related overgrowth spectrum. -

Inborn genetic diseases

Pathogenic:1

Sep 26, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1030G>A (p.V344M) alteration is located in exon 5 (coding exon 4) of the PIK3CA gene. This alteration results from a G to A substitution at nucleotide position 1030, causing the valine (V) at amino acid position 344 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a mosaic or heterozygous mutation, de novo when parents were tested, in multiple individuals with megalencephaly, macrocephaly, hemihypertrophy, polydactyly, autism, speech delay, and/or dysmorphic facial features (Mirzaa, 2016; De Graer, 2020; Cooley Coleman, 2023; DECIPHER). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Diaphragmatic eventration;C0020534:Hypertelorism;C0266166:Intestinal duplication;C3805727:Megalencephaly, autosomal dominant;C4024297:Abnormality of the hairline

Pathogenic:1

Jun 06, 2019

Center of Human Genetics, Erasme Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The c.1030G>A p.(Val344Met) has been identified by our team in a fetus showing megalencephaly, left diaphragmatic eventration, facial dysmorphism (hypertelorism, abnormal hair line implantation) and duplication of distal portion of the small bowel. The variant arose as a de novo event and it was present in several fetal tissues. In addition, the c.1030G>A p.(Val344Met) variant has been previously reported at de novo constitutional state in two patients presenting megalencephaly (Mirzaa et al., 2016; Yeung et al., 2017). Moreover, this variant is listed in the Catalogue of Somatic Mutations in Cancer (COSMIC accession: COSM253279, COSM253280) and found in several types of carcinoma, glioma and angiosarcoma. Moreover, this variant is not present in frequency databases (gnomAD, Exome Variant Server) and several prediction tools (PolyPhen2, SIFT, LRT, MutationTaster, etc) agree to predict this change as deleterious. Overall, the c.1030G>A p.(Val344Met) variant meets our criteria to be classified as pathogenic. -

Cowden syndrome

Pathogenic:1

Jul 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 376498). This missense change has been observed in individual(s) with megalencephaly (PMID: 27631024; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 344 of the PIK3CA protein (p.Val344Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.071

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

-0.016

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

9.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.70

N;.

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.012

D;.

Polyphen

1.0

D;.

Vest4

0.73

MutPred

0.40

Gain of MoRF binding (P = 0.0949);Gain of MoRF binding (P = 0.0949);

MVP

0.74

MPC

1.9

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.73

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over