Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006218.2 | Alternative | 3724 nt | 158–3364 |
| NM_006218.3 | Alternative | 9104 nt | 158–3364 |
| NM_006218.4 | MANE Select | 9259 nt | 324–3530 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PIK3CA R662M variant has not been functionally characterized, and its biological significance remains unknown.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.02 | -73 bp |
| Donor Loss (DL) | 0.01 | 30 bp |
| Acceptor Gain (AG) | 0.01 | -122 bp |
| Donor Gain (DG) | 0.0 | 64 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: “Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.” The evidence for this variant shows: NM_006218.4:c.1985G>T is a missense change (R662M), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet the definition of a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: “Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.” The evidence for this variant shows: no known pathogenic variant resulting in R662M or any other change at codon 662 has been reported. Therefore, this criterion is not applied at Not Applied strength because there is no prior established pathogenic variant at this amino acid.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2_Strong is: “De novo (both maternity and paternity confirmed) in a patient with the disease” and for PS2_Moderate if partial criteria are met. The evidence for this variant shows: there is no information regarding de novo occurrence in a proband or parental testing. Therefore, this criterion is not applied at Not Applied strength due to lack of de novo evidence.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: “Well-validated functional studies showing a damaging effect on gene or gene product” with specifications for assay validation. The evidence for this variant shows: no functional assay data are available for R662M in PIK3CA. Therefore, this criterion is not applied at Not Applied strength because required functional study data are missing.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: “Case data meeting phenotype criteria with points assigned for each case absent from controls.” The evidence for this variant shows: no clinical case reports or phenotype data are available. Therefore, this criterion is not applied at Not Applied strength due to absence of case/phenotype evidence.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1_Supporting is: “Residues affecting critical functional domains provided in Table 4 for each gene.” The evidence for this variant shows: R662 is not listed among known critical mutational hotspots or domains for PIK3CA. Therefore, this criterion is not applied at Not Applied strength because the residue is not in a defined critical domain.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2_Supporting is: “Absent/rare from controls in an ethnically-matched cohort population sample (≥1).” The evidence for this variant shows: MAF = 0% in gnomAD, 1000 Genomes, and ExAC; the variant is absent from population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: “Detected in trans with a pathogenic variant for a recessive disorder.” The evidence for this variant shows: PIK3CA-related conditions are autosomal dominant and there is no report of trans configuration with a pathogenic variant. Therefore, this criterion is not applied at Not Applied strength.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: “Protein length changes due to in-frame indels or stop-loss variants.” The evidence for this variant shows: R662M is a missense substitution with no change in protein length. Therefore, this criterion is not applied at Not Applied strength.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: “Novel missense change at an amino acid residue where a different missense change is pathogenic.” The evidence for this variant shows: no other pathogenic variants at residue 662 have been reported. Therefore, this criterion is not applied at Not Applied strength.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: “Assumed de novo, but without confirmation of paternity and maternity.” The evidence for this variant shows: no parental testing or de novo assumption data. Therefore, this criterion is not applied at Not Applied strength.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: “Cosegregation with disease in multiple affected family members.” The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied at Not Applied strength.
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2_Supporting is: “Missense constraint computed in ExAC/gnomAD; award PP2 if Z-score >3.09 (applicable to PIK3CA).” The evidence for this variant shows: PIK3CA has a missense Z-score >3.09 indicating constraint and R662M is a missense change. Therefore, this criterion is applied at Supporting strength because the gene is missense-constrained and the variant is a missense substitution.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: “Multiple lines of computational evidence support a deleterious effect.” The evidence for this variant shows: in silico predictions are mixed (PolyPhen-2 ‘probably damaging’, REVEL 0.66 vs. CADD 5.59, MetaSVM/MetaLR ‘tolerant’). Therefore, this criterion is not applied at Not Applied strength due to conflicting computational evidence.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: “Patient’s phenotype or family history highly specific for a gene.” The evidence for this variant shows: no patient phenotype or clinical presentation data are provided. Therefore, this criterion is not applied at Not Applied strength.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: “Reputable source reports variant as pathogenic.” The evidence for this variant shows: ClinVar entries classify R662M as VUS, not pathogenic. Therefore, this criterion is not applied at Not Applied strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: “Allele frequency >0.0926% in control populations.” The evidence for this variant shows: MAF = 0% in population databases. Therefore, this criterion is not applied at Not Applied strength.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1_Strong is: “Allele frequency >0.0185% in control populations.” The evidence for this variant shows: MAF = 0%, well below the threshold. Therefore, this criterion is not applied at Not Applied strength.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2_Strong is: “≥3 homozygotes in gnomAD or ≥3 heterozygotes in well-phenotyped family members.” The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at Not Applied strength.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: “Well‐validated functional studies show no damaging effect.” The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied at Not Applied strength.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: “Lack of segregation in affected members of a family.” The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: “Missense variant in gene where only truncating variants cause disease.” The evidence for this variant shows: PIK3CA disease mechanism is often gain‐of‐function missense. Therefore, this criterion is not applied at Not Applied strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: “Observed in cis or trans with a known pathogenic variant.” The evidence for this variant shows: no information on co-occurrence with pathogenic variants. Therefore, this criterion is not applied at Not Applied strength.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: “In-frame indel in repetitive region without a known function.” The evidence for this variant shows: R662M is not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: “Applicable only to synonymous, intronic, or UTR variants if ≥2 of 3 splice tools predict no effect.” The evidence for this variant shows: R662M is an exonic missense change, not eligible. Therefore, this criterion is not applied at Not Applied strength.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: “Variant found in a case with an alternate molecular basis for disease.” The evidence for this variant shows: no such alternate molecular basis reported. Therefore, this criterion is not applied at Not Applied strength.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: “Reputable source reports variant as benign.” The evidence for this variant shows: no reputable benign classification; ClinVar lists VUS. Therefore, this criterion is not applied at Not Applied strength.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: “Synonymous or non-coding intronic variants with low conservation (PhyloP <0.1).” The evidence for this variant shows: R662M is a missense change. Therefore, this criterion is not applied at Not Applied strength.