rs11709323

Variant names:

• chr3-179198731-T-C
• rs11709323
• NM_006218.4:c.-76-19T>C

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.-76-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 634,656 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (42 hom., cov: 32)
  • Exomes 𝑓: 0.014 (256 hom.)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.27
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-179198731-T-C is Benign according to our data. Variant chr3-179198731-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1181592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.-76-19T>C		intron_variant	Intron 1 of 20	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.-76-19T>C		intron_variant	Intron 1 of 20		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.-76-19T>C		intron_variant	Intron 1 of 20	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1343 AN: 152198 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00738

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.0136 AC: 6555 AN: 482340 Hom.: 256 Cov.: 6 AF XY: 0.0133 AC XY: 3320 AN XY: 249972

African (AFR) AF: 0.00147 AC: 19 AN: 12934

American (AMR) AF: 0.00287 AC: 40 AN: 13944

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 28 AN: 13114

East Asian (EAS) AF: 0.119 AC: 3651 AN: 30606

South Asian (SAS) AF: 0.00524 AC: 180 AN: 34344

European-Finnish (FIN) AF: 0.00253 AC: 110 AN: 43478

Middle Eastern (MID) AF: 0.00197 AC: 7 AN: 3552

European-Non Finnish (NFE) AF: 0.00746 AC: 2269 AN: 304048

Other (OTH) AF: 0.00954 AC: 251 AN: 26320

GnomAD4 genome AF: 0.00879 AC: 1339 AN: 152316 Hom.: 42 Cov.: 32 AF XY: 0.00934 AC XY: 696 AN XY: 74490

African (AFR) AF: 0.00180 AC: 75 AN: 41578

American (AMR) AF: 0.00484 AC: 74 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.117 AC: 608 AN: 5190

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4832

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00738 AC: 502 AN: 68008

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00765 Hom.: 4

Bravo AF: 0.00954

Asia WGS AF: 0.0360 AC: 125 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 04, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.51
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs11709323; hg19: chr3-178916519; COSMIC: COSV55877393;