PIK3CA c.2985C>T, p.Ala995=
NM_006218.4:c.2985C>T
COSMIC ID: COSM9312221
Variant of Uncertain Significance (VUS)
This synonymous PIK3CA variant is rare (PM2 Supporting) and predicted to have no splicing impact (BP4 Supporting), with no other pathogenic or benign evidence. The evidence is insufficient for pathogenic or benign classification, resulting in VUS.
ACMG/AMP Criteria Applied
PM2
BP4
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.2985C>T
Protein Change
A995=
Location
Exon 21
(Exon 21 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM9312221
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.2985C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0607%
Common
Highest in Population
Ashkenazi Jewish
0.377%
Common
Global: 0.0607%
Ashkenazi Jewish: 0.377%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 280120Alt: 170Homozygotes: 2
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0607%, 170/280120 alleles, homozygotes = 2) and at a higher frequency in the Ashkenazi Jewish population (MAF= 0.377%, 39/10350 alleles, homozygotes = 1). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
1 LB
3 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratories) and as Likely benign (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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.53
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1 rule is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows it is synonymous (A995=) and not predicted to affect splice sites at canonical positions. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 rule is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no amino acid change (synonymous), so PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires confirmed de novo occurrence with maternity and paternity and/or tissue mosaicism evidence. No de novo or mosaicism data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 rule is: "Well‐established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." No functional studies are available for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires phenotypic case‐control evidence with point scoring and absence from controls (PM2). No case reports or statistical evidence exist for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 Supporting is: "Residues affecting critical functional domains provided in Table 4 for each gene." This variant is synonymous and does not affect a critical domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting is: "Absent/rare from controls in an ethnically-matched cohort population sample (≥1)." The evidence for this variant shows a maximum gnomAD MAF of 0.0607% (170/280,120 alleles, 2 homozygotes), which is below common thresholds and qualifies as rare. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 rule is: "For recessive disorders, detected in trans with a pathogenic variant." No information on trans configuration with another variant is available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 rule is: "Protein length changes due to in-frame deletions/insertions." This variant is synonymous and does not change protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 Moderate is: "Novel missense change at an amino acid where a different missense change is pathogenic." This variant is synonymous. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 rule is: "Assumed de novo, without confirmation of paternity and maternity." No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 rule is: "Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines for PIK3CA, PP2 Supporting is: "Missense constraint z-score >3.09." This variant is synonymous, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 rule is: "Multiple lines of computational evidence support a deleterious effect." In silico predictors show predominantly benign results (CADD 0.53, SpliceAI 0.12), so no evidence for deleterious effect. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 rule is: "Patient’s phenotype or family history highly specific for a disease with a single genetic cause." No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 rule is: "Reputable source reports variant as pathogenic without evidence." ClinVar reports are conflicting (Benign, Likely Benign, VUS). No single reputable source supports pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 Stand Alone is: "Allele frequency >0.0926%." The variant MAF is 0.0607%, below the threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 Strong is: "Allele frequency >0.0185%." The variant MAF of 0.0607% (0.000607) is below 0.0185 (1.85%). Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 Strong is: "≥3 homozygotes in gnomAD or ≥3 heterozygous well-phenotyped family members." Only 2 homozygotes are observed. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 Strong requires well-established functional studies showing no damaging effect. No such studies exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 rule is: "Lack of segregation in affected members of a family." No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 rule is: "Missense variant in a gene where only loss-of-function causes disease." This variant is synonymous. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 rule is: "Observed in trans with a pathogenic variant (for dominant) or in cis with pathogenic variant." No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 rule is: "In-frame deletions/insertions in a repetitive region without known function." This variant is synonymous. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 Supporting is: "For synonymous variants, if two of three splicing tools predict no impact on splicing." SpliceAI predicts minimal impact (0.12), and in silico splicing predictors are concordant for no effect. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 rule is: "Variant found in a case with an alternate molecular basis for disease." No such evidence exists. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 rule is: "Reputable source reports variant as benign without evidence." ClinVar submissions are conflicting; no single source meets criteria. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 Supporting is: "Synonymous variant at non-conserved nucleotide (PhyloP <0.1)." No conservation data (PhyloP) are provided. Therefore, BP7 is not applied.