NM_006218.4:c.112C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_006218.4(PIK3CA):c.112C>T(p.Arg38Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 7.52

Publications

79 publications found

Variant links:

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

PIK3CA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a domain PI3K-ABD (size 89) in uniprot entity PK3CA_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_006218.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-179198938-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376492.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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.112C>T	p.Arg38Cys	missense	Exon 2 of 21	NP_006209.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.112C>T	p.Arg38Cys	missense	Exon 2 of 21	ENSP00000263967.3
PIK3CA	ENST00000643187.1		c.112C>T	p.Arg38Cys	missense	Exon 2 of 22	ENSP00000493507.1
PIK3CA	ENST00000468036.1	TSL:3	c.112C>T	p.Arg38Cys	missense	Exon 2 of 2	ENSP00000417479.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

248624

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725880

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

85976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109766

Other (OTH)

AF:

0.00

AC:

AN:

60310

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 24, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 29438965, 26619011, 31565188, 33148674, 32269842, 34693559, 35070505, 35626111)

Cowden syndrome

Uncertain:1

May 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine with cysteine at codon 38 of the PIK3CA protein (p.Arg38Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs749415085, ExAC 0.002%). This variant has not been reported in the literature in individuals with PIK3CA-related conditions. ClinVar contains an entry for this variant (Variation ID: 376493). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Colorectal cancer

Other:1

Jul 11, 2016

Genome Sciences Centre, British Columbia Cancer Agency

Significance:

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

-0.035

MutationAssessor

Benign

1.9

PhyloP100

7.5

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.74

Sift

Benign

0.072

Sift4G

Benign

0.061

Polyphen

1.0

Vest4

0.80

MutPred

0.74

Gain of sheet (P = 0.0827)

MVP

0.89

MPC

2.2

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.83

Mutation Taster

=72/28

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over