rs397514565

Variant names:

• chr3-179204576-G-A
• rs397514565
• NM_006218.4:c.1133G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-179204576-G-A
• chr3-179204576-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1133G>A​(p.Cys378Tyr) 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.50

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• 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 hereditary breast carcinoma, vascular malformation, Cowden disease, Cowden syndrome 5, CLOVES syndrome, familial ovarian cancer, megalencephaly-capillary malformation-polymicrogyria syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 3-179204576-G-A is Pathogenic according to our data. Variant chr3-179204576-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1133G>A	p.Cys378Tyr	missense_variant	Exon 6 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1133G>A	p.Cys378Tyr	missense_variant	Exon 6 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1133G>A	p.Cys378Tyr	missense_variant	Exon 6 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1363934 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 684336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:3

Dec 20, 2018

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 26637981). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039704). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024). A different missense change at the same codon (p.Cys378Arg) has been reported to be associated with PIK3CA related disorder (ClinVar ID: VCV000917489). The variant was detected at ~13% allele frequency, suggesting mosaic state. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

PIK3CA related overgrowth syndrome Pathogenic:2

Dec 08, 2014

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Care4Rare-SOLVE, CHEO

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

PIK3CA-related disorder Pathogenic:1

Aug 30, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.1133G>A variant is predicted to result in the amino acid substitution p.Cys378Tyr. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. -

Epidermal nevus Pathogenic:1

Aug 08, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2_Very Strong, PM2, PP2, PP3 -

not provided Pathogenic:1

Sep 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27631024, 22729224, 28151489, 36919607) -

Cowden syndrome Pathogenic:1

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 39704). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome (MCAP) and symptoms consistent with PIK3CA-related overgrowth syndrome (PMID: 22729224, 27631024, 28151489). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 378 of the PIK3CA protein (p.Cys378Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.65
Sift	Benign	0.088	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.87	P;.
Vest4		0.97
MutPred		0.63		Loss of catalytic residue at P377 (P = 0.0134);Loss of catalytic residue at P377 (P = 0.0134);
MVP		0.85
MPC		1.7
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.70
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs397514565; hg19: chr3-178922364; COSMIC: COSV55952006;