VCV000526641.30 - ClinVar

NM_006218.4(PIK3CA):c.436G>A (p.Val146Ile)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (3)

3 out of 3 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006218.4(PIK3CA):c.436G>A (p.Val146Ile)

Variation ID: 526641 Accession: VCV000526641.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179199773 (GRCh38) [ NCBI UCSC ] 3: 178917561 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 28, 2018	Jun 20, 2026	Aug 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.436G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Val146Ile	missense
NC_000003.12:g.179199773G>A
NC_000003.11:g.178917561G>A
NG_012113.2:g.56251G>A
LRG_310:g.56251G>A
LRG_310t1:c.436G>A

... more HGVS ... less HGVS

Protein change

V146I

Other names

Canonical SPDI

NC_000003.12:179199772:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00005

Links

ClinGen: CA2710540 dbSNP: rs755969956 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PIK3CA		No evidence available	No evidence available	GRCh38 GRCh37	1608	1647

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cowden syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 31, 2022	RCV000631220.7
CLAPO syndrome CLOVES syndrome Carcinoma of colon Congenital macrodactylia Cowden syndrome 5 Epidermal nevus Familial cancer of breast Hepatocellular carcinoma Lung carcinoma Megalencephaly-capillary malformation-polymicrogyria syndrome Neoplasm of stomach Ovarian neoplasm Seborrheic keratosis	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764478.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2023	RCV003432657.22

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 31, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial cancer of breast Colorectal cancer Hepatocellular carcinoma Congenital macrodactylia Epidermal nevus Ovarian cancer Seborrheic keratosis Lung cancer Megalencephaly-capillary malformation-polymicrogyria syndrome CLOVES syndrome CLAPO syndrome Gastric cancer Cowden syndrome 5	Fulgent Genetics, Fulgent Genetics Accession: SCV000895549.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30 pmc: 4544753 pmc: 4544753 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Aug 31, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cowden syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000752234.3 First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023	Comment: show This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 146 of the PIK3CA protein (p.Val146Ile). This variant is present in population databases (rs755969956, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PIK3CA-related conditions. ClinVar contains an entry for this variant (Variation ID: 526641). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Aug 01, 2023) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV004149434.22 First in ClinVar: Nov 20, 2023 Last updated: Jun 20, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Comment:

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 146 of the PIK3CA protein (p.Val146Ile). This variant is present in population databases (rs755969956, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PIK3CA-related conditions. ClinVar contains an entry for this variant (Variation ID: 526641). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs755969956 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 06, 2026