Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001837029 | SCV001949965 | uncertain significance | Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes | 2022-02-12 | reviewed by expert panel | curation | The c.1631C>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Thr544Asn). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_M; PMIDs: 25722288, 22357840; identified in 1 individual with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s), 6 tumor samples in the literature and COSMIC). 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). This variant has been observed in cis with the variant c.1624G>A (p.Glu542Lys) (PMID: 25722288), (which is classified as pathogenic by the ClinGen BMEP) in an individual with features consistent with this disorder (BP2). In summary, this variant meets the criteria to be classified as Uncertain significance 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, PS4_M, PP2, BP2; 3 points (VCEP specifications version 1; Approved: 1/31/2021) |