3-179203547-A-G

Variant names:

• chr3-179203547-A-G
• rs765030404
• NM_006218.4:c.817A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM5 PP2 BP4_Moderate BP6 BS2

The ENST00000263967.4(PIK3CA):​c.817A>G​(p.Ile273Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,460,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I273M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PIK3CA ENST00000263967.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.29
• Publications: 4 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_benign. The variant received -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-179203549-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4291761.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the PIK3CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 5.5986 (above the threshold of 3.09). Trascript score misZ: 6.1406 (above the threshold of 3.09). GenCC associations: The gene is linked to megalencephaly-capillary malformation-polymicrogyria syndrome, vascular malformation, Cowden syndrome 5, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, Cowden disease, hereditary breast carcinoma, familial ovarian cancer.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19501686).
• BP6: Variant 3-179203547-A-G is Benign according to our data. Variant chr3-179203547-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 571273.
• BS2: High AC in GnomAdExome4 at 44 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000263967.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.817A>G	p.Ile273Val	missense	Exon 5 of 21	NP_006209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.817A>G	p.Ile273Val	missense	Exon 5 of 21	ENSP00000263967.3
	PIK3CA	ENST00000643187.1		c.817A>G	p.Ile273Val	missense	Exon 5 of 22	ENSP00000493507.1
	PIK3CA	ENST00000674534.1		n.571A>G		non_coding_transcript_exon	Exon 1 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248150 AF XY: 0.0000148

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: 0.0000445

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460772 Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 27 AN XY: 726736

African (AFR) AF: 0.0000598 AC: 2 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111612

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cowden syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.67	N
PhyloP100		3.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.063
MVP		0.27
MPC		0.65
ClinPred		0.20	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.34
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs765030404; hg19: chr3-178921335; COSMIC: COSV106052780;