rs587776802

Variant names:

• chr3-179234358-G-GA
• rs587776802
• NM_006218.4:c.3203dupA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_006218.4(PIK3CA):​c.3203dupA​(p.Asn1068LysfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004176955: "This variant results in increased cell proliferation, migration, and Akt phosphorylation compared to wild-type gene product and increased transformation ability in several different cell lines in culture (Jin N et al., PMID:34779417" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.85
• Publications: 24 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 Submitted by: ClinGen
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.000935 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004176955: "This variant results in increased cell proliferation, migration, and Akt phosphorylation compared to wild-type gene product and increased transformation ability in several different cell lines in culture (Jin N et al., PMID: 34779417; Ng PK et al., PMID: 29533785)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-179234358-G-GA is Pathogenic according to our data. Variant chr3-179234358-G-GA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13658.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.3203dupA	p.Asn1068LysfsTer5	frameshift	Exon 21 of 21	NP_006209.2	P42336

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.3203dupA	p.Asn1068LysfsTer5	frameshift	Exon 21 of 21	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.3233dupA	p.Asn1078LysfsTer5	frameshift	Exon 21 of 21	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.3203dupA	p.Asn1068LysfsTer5	frameshift	Exon 22 of 22	ENSP00000546604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Gastric cancer (1)
1	-	-	Hepatocellular carcinoma (1)
1	-	-	PIK3CA related overgrowth syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587776802; hg19: chr3-178952146; COSMIC: COSV55878665; COSMIC: COSV55878665;