The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

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

CA333572

31944 (ClinVar)

Gene: PIK3CA
Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance Mode: Autosomal dominant inheritance (mosaic)
UUID: 7ffcf400-d46a-4637-be35-8721447aa249
Approved on: 2022-02-12
Published on: 2022-02-12

HGVS expressions

NM_006218.4:c.1624G>A
NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)
NC_000003.12:g.179218294G>A
CM000665.2:g.179218294G>A
NC_000003.11:g.178936082G>A
CM000665.1:g.178936082G>A
NC_000003.10:g.180418776G>A
NG_012113.2:g.74772G>A
ENST00000263967.4:c.1624G>A
ENST00000462255.2:n.86G>A
ENST00000643187.1:c.1624G>A
ENST00000674534.1:n.1378G>A
ENST00000674622.1:n.127G>A
ENST00000675467.1:n.4431G>A
ENST00000675786.1:c.*191G>A
ENST00000263967.3:c.1624G>A
NM_006218.2:c.1624G>A
NM_006218.3:c.1624G>A

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"
Met criteria codes 4
PS2_Moderate PP2 PS4 PM2_Supporting
Not Met criteria codes 22
BA1 BP7 BP5 BP4 BP1 BP3 BP2 BS2 BS4 BS1 BS3 PVS1 PP4 PP3 PP1 PM6 PM4 PM3 PM1 PM5 PS3 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
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)
Met criteria codes
PS2_Moderate
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
PIK3CA ExAC constraint z-score is 5.77
PS4
PS4_VS This variant is present in over 1000 entries in COSMIC. Tumor types include Large intestine (427), Breast (402), Urinary tract (102), Endometrium (71), and Lung (54)
PM2_Supporting
The variant is absent from gnomAD with adequate coverage.
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
addressed in PS2
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Variant does not fall in any of the designated functional domains.
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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