Genetic Variant NM_006218.4:c.469_471delAATinsTCA (chr3-179199806-AAT-TCA) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM2PP2

The NM_006218.4(PIK3CA):c.469_471delAATinsTCA (p.Asn157Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N157D: Uncertain_significance (ClinVar VariationId 4861898, 1 star); p.N157S: Uncertain_significance (ClinVar VariationId 580643, 1 star)

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CA
NM_006218.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.87

Publications

0 publications found

Variant links:

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]

PIK3CA Gene-Disease associations (from GenCC):

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
megalencephaly-capillary malformation-polymicrogyria syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
vascular malformation
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 5
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

PIK3CA links:

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new If you want to explore the variant's impact on the transcript NM_006218.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PIK3CA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 6.149). ClinVar shows strong pathogenic missense enrichment: 99 P/LP and 14 B/LB missense entries (ratio 7.1×).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006218.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PIK3CA NM_006218.4	MANE Select	c.469_471delAATinsTCA p.Asn157Ser	missense	N/A	Prot: NP_006209.2 UniProt: P42336

PIK3CA NM_006218.4

MANE Select

HGVSc / HGVSpc.469_471delAATinsTCAp.Asn157Ser

Exon rankN/A

missense

Prot: NP_006209.2UniProt: P42336

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
PIK3CA ENST00000263967.4	TSL:2MANE Select	c.469_471delAATinsTCA p.Asn157Ser	missense	N/A	Prot: ENSP00000263967.3 UniProt: P42336
PIK3CA ENST00000955190.1		c.469_471delAATinsTCA p.Asn157Ser	missense	N/A	Prot: ENSP00000625249.1 UniProt: A0ACI8UU87
PIK3CA ENST00000876545.1		c.469_471delAATinsTCA p.Asn157Ser	missense	N/A	Prot: ENSP00000546604.1 UniProt: P42336

PIK3CA ENST00000263967.4

TSL:2MANE Select

HGVSc / HGVSpc.469_471delAATinsTCAp.Asn157Ser

Exon rankN/A

missense

Prot: ENSP00000263967.3UniProt: P42336

PIK3CA ENST00000955190.1

HGVSc / HGVSpc.469_471delAATinsTCAp.Asn157Ser

Exon rankN/A

missense

Prot: ENSP00000625249.1UniProt: A0ACI8UU87

PIK3CA ENST00000876545.1

HGVSc / HGVSpc.469_471delAATinsTCAp.Asn157Ser

Exon rankN/A

missense

Prot: ENSP00000546604.1UniProt: P42336

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	5.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence