rs1553823718

Variant names:

• chr3-179219986-T-C
• rs1553823718
• NM_006218.4:c.1949T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-179219986-T-C
• chr3-179219986-T-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_006218.4(PIK3CA):​c.1949T>C​(p.Val650Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000759 in 1,449,830 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.74
• 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: 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a domain PIK helical (size 177) in uniprot entity PK3CA_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_006218.4
• 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=0.16839632).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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.1949T>C	p.Val650Ala	missense	Exon 13 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.1949T>C	p.Val650Ala	missense	Exon 13 of 21	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.1979T>C	p.Val660Ala	missense	Exon 13 of 21	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.1949T>C	p.Val650Ala	missense	Exon 14 of 22	ENSP00000546604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000759 AC: 11 AN: 1449830 Hom.: 0 Cov.: 31 AF XY: 0.00000694 AC XY: 5 AN XY: 720714

African (AFR) AF: 0.00 AC: 0 AN: 32786

American (AMR) AF: 0.00 AC: 0 AN: 41640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 82812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000992 AC: 11 AN: 1108446

Other (OTH) AF: 0.00 AC: 0 AN: 59940

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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	0.099
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.98	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.98	N
REVEL	Benign	0.095
Sift	Benign	0.79	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.70		Loss of stability (P = 0.0669)
MVP		0.31
MPC		1.7
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.24
gMVP		0.31
Mutation Taster		=68/32	polymorphism

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: rs1553823718; hg19: chr3-178937774;