Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg)

CA123326

13652 (ClinVar)

Gene: PIK3CA
Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance Mode: Autosomal dominant inheritance (mosaic)
Link to MONDO
UUID: f4d8f50e-a120-47e5-8b69-0a8921149fde

HGVS expressions

NM_006218.4:c.3140A>G
NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg)
NC_000003.12:g.179234297A>G
CM000665.2:g.179234297A>G
NC_000003.11:g.178952085A>G
CM000665.1:g.178952085A>G
NC_000003.10:g.180434779A>G
NG_012113.2:g.90775A>G
ENST00000263967.4:c.3140A>G
ENST00000462255.2:n.2163A>G
ENST00000643187.1:c.*220A>G
ENST00000674534.1:n.4048A>G
ENST00000674622.1:n.1561A>G
ENST00000675467.1:n.5947A>G
ENST00000675786.1:c.*1707A>G
ENST00000675796.1:n.3035A>G
ENST00000263967.3:c.3140A>G
NM_006218.2:c.3140A>G
NM_006218.3:c.3140A>G

Pathogenic

Met criteria codes 6
PM1_Supporting PS3_Moderate PS4 PS2_Moderate PP2 PM2_Supporting
Not Met criteria codes 20
BP7 BP5 BP3 BP4 BP1 BP2 PS1 PP3 PP4 PP1 PVS1 PM4 PM5 PM3 PM6 BA1 BS3 BS4 BS1 BS2

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_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). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25424831). 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, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021)
Met criteria codes
PM1_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3_Moderate
Animal model with increased tumor burden
In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3ca(H1047R) (Pik3ca(e20H1047R)) mutant allele. We found that activation of the latent Pik3ca(H1047R) allele resulted in breast tumors with multiple histological types. PubMed:22370636
Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02) PubMed:23066039
PS4
over 15 tumor samples in COSMIC
57‐year‐old man who came to our attention for an asymmetric segmental overgrowth of the left foot and ankle, characterized by the presence of bone and connective tissue hyperplastic lesions, the patient showed macrosomia of the left foot and ankle, varus leg deformity and lumps around the knee, and hyperplasia on the left sole PubMed:29988677
PS2_Moderate
was identified in the affected tissue sample. In particular, position 3140 was analyzed in a total of 463 reads in both strands and the variant was identified in 43 of these reads, indicating a variant allele frequency of 9.3% PubMed:29988677
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2_Supporting
1 individual in Gnomad
Not Met criteria codes
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
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
BP2
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
PP3
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
PVS1
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
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
was identified in the affected tissue sample. In particular, position 3140 was analyzed in a total of 463 reads in both strands and the variant was identified in 43 of these reads, indicating a variant allele frequency of 9.3% PubMed:29988677
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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
Approved on: 2022-02-11
Published on: 2022-02-11
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.