chr3-179199145-ACCG-A

Variant names:

• chr3-179199145-ACCG-A
• rs1553820399
• NM_006218.4:c.321_323delCCG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_006218.4(PIK3CA):​c.321_323delCCG​(p.Arg108del) variant causes a disruptive inframe deletion 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N107N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.75
• 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 Submitted by: ClinGen
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006218.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-179199145-ACCG-A is Pathogenic according to our data. Variant chr3-179199145-ACCG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456545.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.321_323delCCG	p.Arg108del	disruptive_inframe_deletion	Exon 2 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.321_323delCCG	p.Arg108del	disruptive_inframe_deletion	Exon 2 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.321_323delCCG	p.Arg108del	disruptive_inframe_deletion	Exon 2 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Dec 26, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PIK3CA c.321_323del (p.Arg108del) variant was identified at an allelic fraction consistent with somatic origin. This exact variant, to our knowledge, has not been reported in the medical literature in PROS disorders but has been reported in breast and colon cancer in the cancer database COSMIC (Genomic Mutation ID: COSV55962048). Additionally, similar indels in nearby residues, p.Glu110del and p.Arg108_Ile112del, have been reported in PROS affected individuals and are considered pathogenic (Andreoti TA et al., PMID: 39376044; Kuentz P et al., PMID: 28151489). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. It resides within the adaptor binding domain of PIK3CA that is defined as a critical functional domain (Liu S et al., PMID: 24459181; Lai A et al., PMID: 35997716). The PIK3CA c.321_323del (p.Arg108del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of a single amino acid in a non-repeat region. Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.321_323del (p.Arg108del) variant is classified as likely pathogenic. -

Cowden syndrome Uncertain:1

Aug 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553820399; hg19: chr3-178916933; COSMIC: COSV55962048;