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.2176G>A (p.Glu726Lys)

CA16602910

376476 (ClinVar)

Gene: PIK3CA
Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance Mode: Autosomal dominant inheritance (mosaic)
UUID: 8d9a648c-9ee0-4820-8635-a9b83415906d
Approved on: 2022-02-12
Published on: 2022-02-12

HGVS expressions

NM_006218.4:c.2176G>A
NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys)
NC_000003.12:g.179221146G>A
CM000665.2:g.179221146G>A
NC_000003.11:g.178938934G>A
CM000665.1:g.178938934G>A
NC_000003.10:g.180421628G>A
NG_012113.2:g.77624G>A
ENST00000263967.4:c.2176G>A
ENST00000462255.2:n.638G>A
ENST00000643187.1:c.2176G>A
ENST00000674534.1:n.3084G>A
ENST00000674622.1:n.597G>A
ENST00000675467.1:n.4983G>A
ENST00000675786.1:c.*743G>A
ENST00000263967.3:c.2176G>A
ENST00000462255.1:n.450G>A
NM_006218.2:c.2176G>A
NM_006218.3:c.2176G>A
More

Pathogenic

Met criteria codes 4
PM2_Supporting PS2 PS4 PP2
Not Met criteria codes 22
BS2 PVS1 BS4 BS3 BS1 BP3 BP2 BP4 BP1 BP7 BP5 PS3 PS1 BA1 PP4 PP1 PP3 PM4 PM3 PM1 PM5 PM6

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
The c.2176G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu726Lys). 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). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in at least 15 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 28566443), and is in at least 15 tumor samples in the literature and COSMIC (PMID: 22729224, PMID: 28941273, PMID: 24497998 )). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMIDs: 22729224, 22729224). 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: PM2_P, PP2, PS4_VS, PS2; 14 points (VCEP specifications version 1; Approved: 1/31/2021)
Met criteria codes
PM2_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
PS4
15MCAP, 104 tumors in cosmic

PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
BS2
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
BS1
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
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
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
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
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
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
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
PM6
Curation History
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