rs397517199

Positions:

• chr3-179210186-G-A
• chr3-179210186-G-C
• chr3-179210186-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_006218.4(PIK3CA):​c.1252G>A​(p.Glu418Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E418E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense, splice_region
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 36 pathogenic changes around while only 2 benign (95%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CA. . Gene score misZ 5.5986 (greater than the threshold 3.09). Trascript score misZ 6.1406 (greater than threshold 3.09). GenCC has associacion of gene with 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 3-179210186-G-A is Pathogenic according to our data. Variant chr3-179210186-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45464.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1252G>A	p.Glu418Lys	missense_variant, splice_region_variant	8/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1252G>A	p.Glu418Lys	missense_variant, splice_region_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1252G>A	p.Glu418Lys	missense_variant, splice_region_variant	8/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Oct 10, 2023

The PIK3CA c.1252G>A (p.Glu418Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-related overgrowth spectrum (PROS) disorders (Kuentz P et al., PMID: 28151489; Parker VER et al., PMID: 30270358; Gripp KW et al., PMID: 27191687). This variant has been reported in the ClinVar database as a likely pathogenic variant of somatic origin by one submitter and a variant of uncertain significance by one submitter (ClinVar ID: 45464 ) and has been reported in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV55880477). This variant is absent from the general population (gnomAD v3.1.2), indicating that it is not a common variant. The PIK3CA c.1252G>A (p.Glu418Lys) variant resides within a C2 domain, amino acids 325-484, of PIK3CA that is defined as a critical functional domain (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene is defined by the ClinGen's Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID: 35997716). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.1252G>A (p.Glu418Lys) variant is classified as pathogenic. -

PIK3CA-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

The PIK3CA c.1252G>A variant is predicted to result in the amino acid substitution p.Glu418Lys. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Gripp et al. 2016. PubMed ID: 27191687; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, the p.Glu418Lys variant is located within a kinase domain (p.322-483) critical for p110α protein function, as evaluated by the ClinGen Brain Malformation Variant Curation Expert Panel (Table 3, Lai et al. 2022. PubMed ID: 35997716). Taken together, this variant is interpreted as likely pathogenic. -

CLOVES syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 19, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.84	N;.
REVEL	Uncertain	0.52
Sift	Benign	0.19	T;.
Sift4G	Benign	0.54	T;.
Polyphen		0.98	D;.
Vest4		0.84
MutPred		0.55		Loss of ubiquitination at K416 (P = 0.0211);Loss of ubiquitination at K416 (P = 0.0211);
MVP		0.91
MPC		1.8
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: 49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397517199; hg19: chr3-178927974; COSMIC: COSV55880477;