rs1553821144

Variant names:

• chr3-179203779-A-G
• rs1553821144
• NM_006218.4:c.1049A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-179203779-A-G
• chr3-179203779-A-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1049A>G​(p.Asp350Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D350N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.81
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr3-179203778-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 418658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant 3-179203779-A-G is Pathogenic according to our data. Variant chr3-179203779-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 521363.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	c.1049A>G	p.Asp350Gly	missense_variant	Exon 5 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1049A>G	p.Asp350Gly	missense_variant	Exon 5 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1049A>G	p.Asp350Gly	missense_variant	Exon 5 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Dec 11, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PIK3CA c.1049A>G (p.Asp350Gly) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Goss JA et al., PMID: 31909475; Zhang B et al., PMID: 37658401; Parker VER et al., PMID: 30270358; Gripp KW et al., PMID: 27191687). This variant has been reported in the ClinVar database as pathogenic in a germline state by a single submitter (ClinVar Variation ID: 521363) and it has also been reported in numerous cases in the cancer database COSMIC (Genomic Mutation ID: COSV55877939). This variant is absent from the general population (gnomAD v4.1.0), indicating it is not a common variant. The PIK3CA c.1049A>G (p.Asp350Gly) variant resides within the C2 domain of PIK3CA that is defined as a critical functional domain (Lai et al, PMID: 35997716). The PIK3CA gene is defined by the ClinGen Brain Malformations Variant Curation Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (Lai et al, PMID: 35997716). Another variant in the same codon, c.1048G>A (p.Asp350Asn), has been reported and is considered pathogenic (ClinVar Variation ID: 418658). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.1049A>G (p.Asp350Gly) variant is classified as pathogenic. -

not provided Pathogenic:1

Jan 31, 2023

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 has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Uncertain:1

Oct 21, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		8.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.28	T;.
Polyphen		0.77	P;.
Vest4		0.75
MutPred		0.58		Gain of MoRF binding (P = 0.0416);Gain of MoRF binding (P = 0.0416);
MVP		0.90
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.85
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs1553821144; hg19: chr3-178921567; COSMIC: COSV55877939; COSMIC: COSV55877939;