ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.1035T>A (p.Asn345Lys)

dbSNP: rs121913284
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001172158 SCV001335125 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002502454 SCV002810301 pathogenic Familial cancer of breast; Megalencephaly-capillary malformation-polymicrogyria syndrome; Congenital macrodactylia; Seborrheic keratosis; Epidermal nevus; Ovarian neoplasm; CLAPO syndrome; CLOVES syndrome; Cowden syndrome 5; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Lung cancer 2022-03-23 criteria provided, single submitter clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis RCV003458198 SCV004176944 pathogenic PIK3CA related overgrowth syndrome 2023-10-27 criteria provided, single submitter clinical testing The PIK3CA c.1035T>A (p.Asn345Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in at least three individuals affected with PROS disorders (Parker VER et al., PMID: 30270358, Tian W et al., PMID: 35122151; McNulty SN et al., PMID: 31585106). The PIK3CA c.1035T>A (p.Asn345Lys) variant has been reported in numerous cases in the cancer database COSMIC (COSMIC Genomic Mutation ID COSV55873276 ) and it has been reported in the ClinVar database as pathogenic by two submitters (ClinVar ID: 376050). This variant is absent from the general population (gnomAD V.3.1.2), indicating it is not a common variant. The PIK3CA c.1035T>A (p.Asn345Lys) variant is considered to be a strong oncogenic variant (Gymnopoulos M et al., PMID: 17376864) and resides in the C2 catalytic subunit of PIK3CA that is defined as a critical functional domain (Madsen R et al., PMID: 30197175; Keppler-Noreuil KM et al., PMID: 25557259). Functional in vitro studies show that this variant leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling, indicating that this variant impacts protein function (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene 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 (Lai A et al. PMID: 35997716). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry PIK3CA c.1035T>A (p.Asn345Lys) variant is classified as pathogenic.
MAGI's Lab - Research, MAGI Group RCV001327959 SCV001437635 pathogenic Abnormal cardiovascular system morphology no assertion criteria provided provider interpretation

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