Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001837031 | SCV001949972 | 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.93A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Ile31Met). 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). This variant resides within the adaptor binding domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). This variant has also been shown to exhibit near wild type levels of cell growth and did not promote colony formation, indicating that this variant does not impact protein function (PMID: 26627007) (BS3_P). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_P; identified in 1 tumor sample in the literature and COSMIC (ACC Breast)). 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, PP2, PM1_P, BS3_P, PS4_P; 3 points (VCEP specifications version 1; Approved: 1/31/2021) |