chr3-179221072-A-G

Position:

• chr3-179221072-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_006218.4(PIK3CA):​c.2102A>G​(p.His701Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H701P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-179221072-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376052.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.2102A>G	p.His701Arg	missense_variant	14/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.2102A>G	p.His701Arg	missense_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.2102A>G	p.His701Arg	missense_variant	14/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.29
Sift	Benign	0.22	T;.
Sift4G	Benign	0.52	T;.
Polyphen		0.61	P;.
Vest4		0.75
MutPred		0.71		Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);
MVP		0.87
MPC		2.2
ClinPred		0.66	D
GERP RS		5.4
Varity_R		0.57
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-178938860;