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NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys) AND Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 12, 2022
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001836714.10

Allele description [Variation Report for NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)]

NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)

Gene:
PIK3CA:phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q26.32
Genomic location:
Preferred name:
NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)
Other names:
NM_006218.3(PIK3CA):c.1624G>A; NM_006218.4(PIK3CA):c.1624G>A
HGVS:
  • NC_000003.12:g.179218294G>A
  • NG_012113.2:g.74772G>A
  • NM_006218.4:c.1624G>AMANE SELECT
  • NP_006209.2:p.Glu542Lys
  • LRG_310t1:c.1624G>A
  • LRG_310:g.74772G>A
  • NC_000003.11:g.178936082G>A
  • NM_006218.2:c.1624G>A
  • NM_006218.3:c.1624G>A
  • P42336:p.Glu542Lys
  • NM_006218.2:c.1625G>A
Protein change:
E542K; GLU542LYS
Links:
UniProtKB: P42336#VAR_026173; OMIM: 171834.0009; dbSNP: rs121913273
NCBI 1000 Genomes Browser:
rs121913273
Molecular consequence:
  • NM_006218.4:c.1624G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
gain_of_function_variant [Sequence Ontology: SO:0002053]

Condition(s)

Name:
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Identifiers:
MONDO: MONDO:0100283; MedGen: CN300503

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001949964ClinGen Brain Malformations Variant Curation Expert Panel
reviewed by expert panel

(ClinGen BrainMalform ACMG Specifications v1)		Pathogenic
(Feb 12, 2022) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Brain Malformations Variant Curation Expert Panel, SCV001949964.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1624G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu542Lys). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 22658544). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 25722288, 25681199, 22658544, 29446767, 26851524, 25292196, 23100325; identified in 1 individual with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation, at least 6 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), at least 9 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, and at least 9 tumor samples in the literature and COSMIC). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen 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 (PP2). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PS2_M, PS4_VS, PM2_P, PP2; 12 points (VCEP specifications version 1; Approved: 1/31/2021)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024