NM_006218.4:c.1252G>A

Variant names:

• chr3-179210186-G-A
• rs397517199
• NM_006218.4:c.1252G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The NM_006218.4(PIK3CA):​c.1252G>A​(p.Glu418Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E418E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense, splice_region
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 U:1 O:1
• Conservation: PhyloP100: 9.60
• Publications: 72 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 3-179210186-G-A is Pathogenic according to our data. Variant chr3-179210186-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 45464.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1252G>A	p.Glu418Lys	missense_variant, splice_region_variant	Exon 8 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1252G>A	p.Glu418Lys	missense_variant, splice_region_variant	Exon 8 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1252G>A	p.Glu418Lys	missense_variant, splice_region_variant	Exon 8 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Oct 10, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.1252G>A (p.Glu418Lys) 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 (Kuentz P et al., PMID: 28151489; Parker VER et al., PMID: 30270358; Gripp KW et al., PMID: 27191687). This variant has been reported in the ClinVar database as a likely pathogenic variant of somatic origin by one submitter and a variant of uncertain significance by one submitter (ClinVar ID: 45464 ) and has been reported in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV55880477). This variant is absent from the general population (gnomAD v3.1.2), indicating that it is not a common variant. The PIK3CA c.1252G>A (p.Glu418Lys) variant resides within a C2 domain, amino acids 325-484, of PIK3CA that is defined as a critical functional domain (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene is defined by the ClinGen's Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID: 35997716). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.1252G>A (p.Glu418Lys) variant is classified as pathogenic. -

PIK3CA-related disorder Pathogenic:1

Jan 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PIK3CA c.1252G>A variant is predicted to result in the amino acid substitution p.Glu418Lys. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Gripp et al. 2016. PubMed ID: 27191687; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, the p.Glu418Lys variant is located within a kinase domain (p.322-483) critical for p110α protein function, as evaluated by the ClinGen Brain Malformation Variant Curation Expert Panel (Table 3, Lai et al. 2022. PubMed ID: 35997716). Taken together, this variant is interpreted as likely pathogenic. -

CLOVES syndrome Pathogenic:1

-

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

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	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.84	N;.
REVEL	Uncertain	0.52
Sift	Benign	0.19	T;.
Sift4G	Benign	0.54	T;.
Polyphen		0.98	D;.
Vest4		0.84
MutPred		0.55		Loss of ubiquitination at K416 (P = 0.0211);Loss of ubiquitination at K416 (P = 0.0211);
MVP		0.91
MPC		1.8
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.83
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: 49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397517199; hg19: chr3-178927974; COSMIC: COSV55880477;