Variant: NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg)

CA130573

39808 (ClinVar)

Gene: PIK3R2

Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Inheritance Mode: Autosomal dominant inheritance (mosaic)

UUID: 421e7cec-5414-46bc-82b2-ecde31fd73a0

Approved on: 2022-02-17

Published on: 2022-02-17

HGVS expressions

NM_005027.4:c.1117G>A
NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg)
NC_000019.10:g.18162974G>A
CM000681.2:g.18162974G>A
NC_000019.9:g.18273784G>A
CM000681.1:g.18273784G>A
NC_000019.8:g.18134784G>A
NG_033010.1:g.14797G>A
NG_033010.2:g.14797G>A
ENST00000222254.13:c.1117G>A
ENST00000617130.5:c.*96G>A
ENST00000617642.2:c.*96G>A
ENST00000675271.1:n.63G>A
ENST00000222254.12:c.1117G>A
ENST00000426902.5:c.1117G>A
ENST00000593731.1:c.1117G>A
ENST00000617130.4:n.1117G>A
ENST00000617642.1:n.1117G>A
NM_005027.3:c.1117G>A
NR_073517.1:n.1657G>A
NR_073517.2:n.1672G>A
NR_162071.1:n.1455G>A

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

• Met criteria codes: PS2_Moderate PM2_Supporting PS4 PM1_Supporting

• Not Met criteria codes: PM3 PM4 PM5 PM6 BA1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS3 PS1 PP4 PP1 PP3 PP2

Expert Panel

Brain Malformations VCEP

Criteria Specification Information

Evidence submitted by expert panel

Brain Malformations VCEP

The c.1117G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Gly373Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within the PIK3R2 SH2, sequence homology 2 domain of PIK3R2 that is defined as a critical functional domain by the ClinGen BMEP (PMID: 26860062) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in 2 individuals with macrocephaly (>=2 SD) and Developmental Delay or Intellectual disability with cortical malformation, 13 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: 22729224), and has been identified in over 15 tumor samples in the literature and COSMIC (PMID: 28086757,22729224, 28502725)). This variant has been identified as a de novo occurrence with confirmed parental relationships (PS2_moderate; PMID: 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, PM1_P, PS4_VS, PS2_M; 13 points (VCEP specifications version 1; Approved: 1/31/2021)

Met criteria codes

• PM2_Supporting: absent from gnomAD and ExAC
• PS4: 16 COSMIC, 27 cBioPortal This variant met criteria to meet PS4_VS >16
• PM1_Supporting: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Not Met criteria codes

• PM3: 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
• PM5: 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
• 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
• BS2: 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
• BP2: 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
• 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
• PVS1: 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
• 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
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline