PIK3CA c.1985G>T, p.Arg662Met
NM_006218.4:c.1985G>T
Variant of Uncertain Significance (VUS)
R662M in PIK3CA remains a Variant of Uncertain Significance due to absence of strong or moderate evidence for pathogenicity beyond PM2 (Supporting) and PP2 (Supporting), lack of functional or clinical data, and conflicting computational predictions.
ACMG/AMP Criteria Applied
PM2
PP2
Genetic Information
Gene & Transcript Details
Gene
PIK3CA
Transcript
NM_006218.4
MANE Select
Total Exons
21
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006218.2 | Alternative | 21 exons | Forward |
| NM_006218.3 | Alternative | 21 exons | Forward |
Variant Details
HGVS Notation
NM_006218.4:c.1985G>T
Protein Change
R662M
Location
Exon 13
(Exon 13 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 662 in gene PIK3CA
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.1985G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 662 in gene PIK3CA
Functional Summary
The PIK3CA R662M variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.658
0.658
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingprimateai: D
Benign:
CADD: 5.59metasvm: Tmetalr: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.