rs587776802

Positions:

• chr3-179234358-G-GA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_006218.4(PIK3CA):​c.3203dup​(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 (★).

• 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1204 codons.
• 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 id is 13658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.3203dup	p.Asn1068LysfsTer5	frameshift_variant	21/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.3203dup	p.Asn1068LysfsTer5	frameshift_variant	21/21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.3203dup	p.Asn1068LysfsTer5	frameshift_variant	21/21	2	NM_006218.4	ENSP00000263967	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Aug 21, 2023

The PIK3CA c.3203dup (p.Asn1068LysfsTer5) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in individuals with lung, breast, liver, and bladder cancers (Youssef O et al., PMID: 2819998; Miron A et al., PMID: 20551053; Cizkova Met al., PMID: 22330809; Kachrilas S et al., PMID: 30941989); however, to our knowledge, this variant has not been reported in individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders. This variant has been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55878665). The PIK3CA c.3203dup (p.Asn1068LysfsTer5) variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The PIK3CA c.3203dup (p.Asn1068LysfsTer5) variant resides within the C-terminal chain, A1052-A1068, of PIK3CA. 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). This variant causes a frameshift by duplicating a single nucleotide; however, because this occurs in the last exon, this is not predicted to lead to nonsense-mediated decay. A large number of PI3K/AKT pathway inhibitors are currently under clinical study in both PROS disorders and cancer (Jin N et al., PMID: 34779417; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.3203dup (p.Asn1068LysfsTer5) variant is classified as likely pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 17, 2005

- -

Hepatocellular carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 17, 2005

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776802; hg19: chr3-178952146;