Variant: NM_006218.3(PIK3CA):c.1624G>A (p.Glu542Lys)

CA333572

31944 (ClinVar)

Gene: PIK3CA

Condition: cerebral malformation

Inheritance Mode: Autosomal dominant inheritance (mosaic)

UUID: 7ffcf400-d46a-4637-be35-8721447aa249

Approved on: 2021-02-01

Published on: 2021-09-27

HGVS expressions

NM_006218.3:c.1624G>A
NM_006218.3(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:c.127G>A
ENST00000675467.1:n.4431G>A
ENST00000675786.1:c.*191G>A
ENST00000263967.3:c.1624G>A
NM_006218.2:c.1624G>A
NM_006218.4:c.1624G>A

Pathogenic

• Met criteria codes: PS2_Moderate PS4 PP2 PM2

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

Expert Panel

Brain Malformations VCEP

Criteria Specification Information

Evidence submitted by expert panel

Brain Malformations VCEP

The c.1624G>AG>A p.E542K missense variant in the PIK3CA gene is previously reported in the literature and has been classified as PATHOGENIC. Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PMID: 22658544). This variant has been 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 (PMID: 25722288, PMID: 25681199, PMID: 22658544, PMID: 29446767, PMID: 26851524, PMID: 25292196, PMID: 23100325) (PS4 Met_VS). This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). This gene has a low rate of benign missense changes (PP2).

Met criteria codes

• PS2_Moderate: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: 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
• PM2: 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
• BS2: 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
• BS4: 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
• BP3: 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
• BP2: 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
• BP7: 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
• PS3: 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
• PP3: 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
• PM1: Variant does not fall in any of the designated functional domains.
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: addressed in PS2
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline