NM_006218.4:c.3140A>G

Variant names:

• chr3-179234297-A-G
• rs121913279
• NM_006218.4:c.3140A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1_Supporting PS4 PS2_Moderate PP2 PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID:25424831). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA123326/MONDO:0016054/018

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:43 O:13
• Conservation: PhyloP100: 8.85
• Publications: 3492 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 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

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.3140A>G	p.His1047Arg	missense	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.3140A>G	p.His1047Arg	missense	Exon 21 of 21	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.3170A>G	p.His1057Arg	missense	Exon 21 of 21	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.3140A>G	p.His1047Arg	missense	Exon 22 of 22	ENSP00000546604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248274 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000653 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	CLOVES syndrome (7)
6	-	-	not provided (6)
2	-	-	CLAPO syndrome (2)
2	-	-	Non-small cell lung carcinoma (2)
2	-	-	Ovarian neoplasm (2)
2	-	-	PIK3CA related overgrowth syndrome (2)
1	-	-	Abnormal cardiovascular system morphology (1)
1	-	-	Breast adenocarcinoma (1)
1	-	-	Breast carcinoma (1)
1	-	-	Carcinoma of colon (1)
1	-	-	CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC (1)
1	-	-	Cerebrofacial Vascular Metameric Syndrome (CVMS) (1)
1	-	-	Congenital macrodactylia (1)
1	-	-	Gastric cancer (1)
1	-	-	Hepatocellular carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.60	N
PhyloP100		8.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.019	D
Sift4G	Benign	0.14	T
Polyphen		0.64	P
Vest4		0.72
MutPred		0.63		Gain of MoRF binding (P = 0.0089)
MVP		0.97
MPC		2.4
ClinPred		0.41	T
GERP RS		6.1
Varity_R		0.54
gMVP		0.96
Mutation Taster		=3/97	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: rs121913279; hg19: chr3-178952085; COSMIC: COSV55873195; COSMIC: COSV55873195;