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

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: PM2_Supporting PS2_Moderate PS4 PP2

• Not Met criteria codes: PM6 PM4 PM3 PM1 PM5 PVS1 BS2 BS4 BS1 BS3 BP4 BP1 BP3 BP2 BP7 BP5 PS3 PS1 BA1 PP4 PP3 PP1

Expert Panel

Brain Malformations VCEP

Criteria Specification Information

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

• PM2_Supporting: The variant is absent from gnomAD with adequate coverage.
• PS2_Moderate: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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)
• PP2: PIK3CA ExAC constraint z-score is 5.77

Not Met criteria codes

• 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
• PVS1: 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
• 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
• 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
• 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
• BA1: 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

Approved on: 2022-02-12

Published on: 2022-02-12