rs772110575

Positions:

• chr3-179198938-G-A
• chr3-179198938-G-C
• chr3-179198938-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_006218.4(PIK3CA):​c.113G>A​(p.Arg38His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:7
• Conservation: PhyloP100: 9.54

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 11 ACMG points.

• PM1: In a domain PI3K-ABD (size 89) in uniprot entity PK3CA_HUMAN there are 16 pathogenic changes around while only 4 benign (80%) 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 chr3-179198937-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376496.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 3-179198938-G-A is Pathogenic according to our data. Variant chr3-179198938-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376492.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.113G>A	p.Arg38His	missense_variant	2/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.113G>A	p.Arg38His	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.113G>A	p.Arg38His	missense_variant	2/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248664 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459198 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, single submitter

Submissions by phenotype

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 07, 2024

This sequence change in PIK3CA is predicted to replace arginine with histidine at codon 38, p.(Arg38His). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in adaptor binding domain (PI3K ABD) a region, amino acids 31-108, that is defined as a mutational hotspot. There is a small physicochemical difference between arginine and histidine. PIK3CA , in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0002% (2/1,110,018 alleles) in the European (non-Finnish) population. This variant has been detected in at least one individual with polymicrogyria (Melbourne Health Pathology) and has been reported as a somatic event in at least 40 tumour samples (COSMIC ID: COSV55879949). In vitro functional studies assessing kinase activity (with limited assay validation) demonstrate a gain of function effect for the variant which is weaker than well-established pathogenic gain of function variants (PMID: 15930273, 16339315, 17376864). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.654). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PM1_Supporting, PM2_Supporting, PP2, PP3, PS3_Supporting. -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.029	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0090	D;.;D
Sift4G	Uncertain	0.026	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.69
MutPred		0.69		Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.80
MPC		2.1
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.80

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: rs772110575; hg19: chr3-178916726; COSMIC: COSV55879949; COSMIC: COSV55879949;