chr3-179218294-GAA-AAG

Variant names:

• chr3-179218294-GAA-AAG
• NM_006218.4:c.1624_1626delGAAinsAAG
• PIK3CA p.Glu542Lys

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 15 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5PP2

The NM_006218.4(PIK3CA):c.1624_1626delGAAinsAAG (p.Glu542Lys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.60). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.E542G: Likely_pathogenic (ClinVar VariationId 376475, 2 stars) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. The variant position is a cancer hotspot (cancerhotspots.org): 372 samples carry this exact amino acid change out of 1860 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

PIK3CA Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• vascular malformation

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 5

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PIK3CA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 3 stars).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 19 pathogenic, 1 benign rare missense variants (OR vs. background: 65.0).; ±8 AA neighbourhood: 13 pathogenic, 0 benign (OR vs. background: 135.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.E542G: Likely_pathogenic (ClinVar VariationId 376475, 2 stars)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 6.149). ClinVar shows strong pathogenic missense enrichment: 99 P/LP and 14 B/LB missense entries (ratio 7.1×).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006218.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PIK3CA NM_006218.4	MANE Select	c.1624_1626delGAAinsAAG p.Glu542Lys	missense	N/A	Prot: NP_006209.2 UniProt:

PIK3CA NM_006218.4

MANE Select

HGVSc / HGVSpc.1624_1626delGAAinsAAGp.Glu542Lys

Exon rankN/A

missense

Prot: NP_006209.2UniProt: P42336

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PIK3CA ENST00000263967.4	TSL:2MANE Select	c.1624_1626delGAAinsAAG p.Glu542Lys	missense	N/A	Prot: ENSP00000263967.3 UniProt:
	PIK3CA ENST00000955190.1		c.1654_1656delGAAinsAAG p.Glu552Lys	missense	N/A	Prot: ENSP00000625249.1 UniProt:
	PIK3CA ENST00000876545.1		c.1624_1626delGAAinsAAG p.Glu542Lys	missense	N/A	Prot: ENSP00000546604.1 UniProt:

PIK3CA ENST00000263967.4

TSL:2MANE Select

HGVSc / HGVSpc.1624_1626delGAAinsAAGp.Glu542Lys

Exon rankN/A

missense

Prot: ENSP00000263967.3UniProt: P42336

PIK3CA ENST00000955190.1

HGVSc / HGVSpc.1654_1656delGAAinsAAGp.Glu552Lys

Exon rankN/A

missense

Prot: ENSP00000625249.1UniProt: A0ACI8UU87

PIK3CA ENST00000876545.1

HGVSc / HGVSpc.1624_1626delGAAinsAAGp.Glu542Lys

Exon rankN/A

missense

Prot: ENSP00000546604.1UniProt: P42336

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr3-178936082;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar