3-179198827-T-C

Variant names:

• chr3-179198827-T-C
• NM_006218.4:c.2T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_006218.4(PIK3CA):​c.2T>C​(p.Met1?) variant causes a start lost 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 45 CDS bases. Genomic position: 179198870. Lost 0.014 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.2T>C	p.Met1?	start_lost	Exon 2 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.2T>C	p.Met1?	start_lost	Exon 2 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.2T>C	p.Met1?	start_lost	Exon 2 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cowden syndrome 5 Uncertain:1

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Cowden syndrome 5 (MIM#615108) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) (MIM#602501) (PMID: 22729222, PMID: 30197175). (I) 0107 - This gene is associated with autosomal dominant disease. In addition, MCAP is often associated with post-zygotic mosaicism (OMIM). (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0710 - Another start-loss variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This variant (p.(Met1Val)) has been reported several times as a VUS (ClinVar, LOVD) and observed in an unaffected adult with a family history of breast cancer (Invitae, personal communication). Additionally, this variant, and another start-loss (p.(Met1Leu)) have been observed repeatedly in a cancer cohort (COSMIC). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;D;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.29	T
PROVEAN	Pathogenic	-5.4	D;D;.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		0.92	.;P;.;.
Vest4		0.89
MutPred		0.96		Gain of phosphorylation at M1 (P = 0.0022);Gain of phosphorylation at M1 (P = 0.0022);Gain of phosphorylation at M1 (P = 0.0022);Gain of phosphorylation at M1 (P = 0.0022);
MVP		0.92
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-178916615;