chr3-179218307-A-T

Variant names:

• chr3-179218307-A-T
• rs397517201
• NM_006218.4:c.1637A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_006218.4(PIK3CA):​c.1637A>T​(p.Gln546Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q546H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95

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 9 ACMG points.

• PM1: In a domain PIK helical (size 177) in uniprot entity PK3CA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr3-179218308-G-T is described in Lovd as [Pathogenic].
• 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, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1637A>T	p.Gln546Leu	missense_variant	Exon 10 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1637A>T	p.Gln546Leu	missense_variant	Exon 10 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1637A>T	p.Gln546Leu	missense_variant	Exon 10 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Jun 01, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PIK3CA c.1637A>T (p.Gln546Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported as a somatic variant in 9 cases in the cancer database COSMIC (Genomic Mutation ID: COSV55877455). It is absent from the general population (gnomAD v4.1.0), indicating it is not a common variant. This variant resides within the helical domain of the p110alpha catalytic subunit of PIK3CA and constitutes a mutational hotspot (Madsen R et al., PMID: 30197175; Keppler-Noreuil KM et al., PMID: 25557259; Gymnopoulos M et al., PMID: 17376864). A PIK3CA c.1637A>T (p.Gln546Leu) variant has been annotated as activating and shown to increased transformation ability in two different cell lines (Ng PKS et al., PMID: 29533785). Additionally, the PIK3CA gene is defined by the ClinGen 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). Multiple variants in the same codon, p.Gln546Arg, p.Gln546Glu, p.Gln546His, p.Gln546Lys, and p.Gln546Pro, have been reported and are considered pathogenic (ClinVar Variation IDs: 45466, 13654, 376491, 13657, 375898; Mirzaa G et al., PMID: 27631024). A large number of PI3K/AKT pathway inhibitors are currently under clinical study in both PROS disorders and cancer (Jin N et al., PMID: 34779417; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358)Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.1637A>T (p.Glu546Leu) variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D;.
REVEL	Uncertain	0.64
Sift	Benign	0.17	T;.
Sift4G	Benign	0.17	T;.
Polyphen		0.99	D;.
Vest4		0.76
MutPred		0.74		Loss of ubiquitination at K548 (P = 0.0464);Loss of ubiquitination at K548 (P = 0.0464);
MVP		0.79
MPC		2.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.68

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: rs397517201; hg19: chr3-178936095; COSMIC: COSV55877455; COSMIC: COSV55877455;