rs17849071

Variant names:

• chr3-179218439-T-G
• rs17849071
• NM_006218.4:c.1664+105T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006218.4(PIK3CA):​c.1664+105T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0727 in 808,138 control chromosomes in the GnomAD database, including 2,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene PIK3CA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.080 (513 hom., cov: 32)
  • Exomes 𝑓: 0.071 (1740 hom.)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.397
• Publications: 10 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

Specifications for PIK3CA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-179218439-T-G is Benign according to our data. Variant chr3-179218439-T-G is described in ClinVar as Benign. ClinVar VariationId is 1274886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

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.1664+105T>G		intron	N/A	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.1664+105T>G		intron	N/A	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.1694+105T>G		intron	N/A	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.1664+105T>G		intron	N/A	ENSP00000546604.1

Frequencies

GnomAD3 genomes AF: 0.0797 AC: 12110 AN: 151974 Hom.: 513 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0916

Gnomad ASJ AF: 0.0465

Gnomad EAS AF: 0.0991

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.0678

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0703

GnomAD4 exome AF: 0.0711 AC: 46626 AN: 656044 Hom.: 1740 AF XY: 0.0713 AC XY: 23849 AN XY: 334514

African (AFR) AF: 0.110 AC: 1728 AN: 15776

American (AMR) AF: 0.108 AC: 1750 AN: 16180

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 689 AN: 13884

East Asian (EAS) AF: 0.0749 AC: 2346 AN: 31334

South Asian (SAS) AF: 0.0781 AC: 2472 AN: 31648

European-Finnish (FIN) AF: 0.0705 AC: 3083 AN: 43714

Middle Eastern (MID) AF: 0.0888 AC: 243 AN: 2736

European-Non Finnish (NFE) AF: 0.0683 AC: 32110 AN: 469872

Other (OTH) AF: 0.0714 AC: 2205 AN: 30900

GnomAD4 genome AF: 0.0797 AC: 12128 AN: 152094 Hom.: 513 Cov.: 32 AF XY: 0.0806 AC XY: 5997 AN XY: 74362

African (AFR) AF: 0.104 AC: 4324 AN: 41538

American (AMR) AF: 0.0925 AC: 1413 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0465 AC: 161 AN: 3464

East Asian (EAS) AF: 0.0989 AC: 513 AN: 5186

South Asian (SAS) AF: 0.0806 AC: 389 AN: 4828

European-Finnish (FIN) AF: 0.0678 AC: 719 AN: 10604

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0637 AC: 4321 AN: 67884

Other (OTH) AF: 0.0696 AC: 147 AN: 2112

Alfa AF: 0.0773 Hom.: 60

Bravo AF: 0.0841

Asia WGS AF: 0.0770 AC: 267 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.65
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs17849071; hg19: chr3-178936227; COSMIC: COSV104381265;