PIK3CA c.1813A>G, p.Asn605Asp
NM_006218.4:c.1813A>G
Variant of Uncertain Significance (VUS)
The PIK3CA c.1813A>G (N605D) variant is classified as VUS based solely on PM2_Supporting (absent from population controls). No additional pathogenic or benign criteria are met under PIK3CA VCEP guidelines.
ACMG/AMP Criteria Applied
PM2
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.1813A>G
Protein Change
N605D
Location
Exon 12
(Exon 12 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 605 in gene PIK3CA
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.1813A>G
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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 605 in gene PIK3CA
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.21
0.21
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
Benign:
CADD: 3.86polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1 is a null variant in a gene where loss of function is a known disease mechanism. The evidence for this variant shows it is a missense change (N605D), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 is the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. The evidence for this variant shows no known pathogenic N605D at this residue. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires confirmed de novo occurrence with parental and tissue evidence. The evidence for this variant shows no de novo or parental data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires well-validated functional studies demonstrating a damaging effect. The evidence for this variant shows no functional data. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 is based on case counts and phenotype points for variants absent from controls. The evidence for this variant shows no reported cases or phenotype data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1_Supporting applies to residues affecting critical functional domains per Table 4. The evidence for this variant shows N605 is not in a defined hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting is applied for absent or rare variants from controls in ethnically matched populations. The evidence for this variant shows it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with observed trans occurrences. The evidence for this variant shows no recessive context or trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes. The evidence for this variant shows a single amino acid substitution without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5_Moderate applies for novel missense changes at residues with known pathogenic missense changes. The evidence for this variant shows no other pathogenic variants at residue N605. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation. The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 supports segregation in affected family members. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, PP2_Supporting applies if ExAC/gnomAD missense constraint z-score >3.09. The evidence for this variant shows no z-score data provided. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 requires multiple computational predictions supporting a deleterious effect. The evidence for this variant shows predominantly benign in silico predictions. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies to patient phenotype highly specific to a gene. The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to reputable source classifications. The evidence for this variant shows no ClinVar or expert classification. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies for allele frequency >0.0926%. The evidence for this variant shows 0% frequency. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies for allele frequency >0.0185%. The evidence for this variant shows 0% frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires ≥3 well-phenotyped heterozygotes or homozygotes in controls. The evidence for this variant shows none. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well-validated functional studies showing no damaging effect. The evidence for this variant shows no such functional data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for lack of segregation in affected members. The evidence for this variant shows no segregation information. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating pathogenic variants are known. The evidence for this variant shows PIK3CA pathogenicity is gain-of-function, not truncation. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in cis/trans with a pathogenic variant. The evidence for this variant shows no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows a missense SNP. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 only applies to synonymous or intronic variants when splicing tools show no impact. The evidence for this variant shows a missense change. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant occurs in a case with an alternate molecular basis. The evidence for this variant shows no such context. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to assertions from reputable sources without evidence. The evidence for this variant shows no such assertions. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies only to synonymous or intronic variants with low conservation. The evidence for this variant shows a missense change. Therefore, this criterion is not applied.