VCV001703510.5 - ClinVar

NM_006218.4(PIK3CA):c.344G>T (p.Arg115Leu)

Germline

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.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006218.4(PIK3CA):c.344G>T (p.Arg115Leu)

Variation ID: 1703510 Accession: VCV001703510.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179199169 (GRCh38) [ NCBI UCSC ] 3: 178916957 (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	Sep 3, 2022	Feb 20, 2024	Oct 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.344G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Arg115Leu	missense
NC_000003.12:g.179199169G>T
NC_000003.11:g.178916957G>T
NG_012113.2:g.55647G>T
LRG_310:g.55647G>T
LRG_310t1:c.344G>T

... more HGVS ... less HGVS

Protein change

R115L

Other names

Canonical SPDI

NC_000003.12:179199168:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Links

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	1303	1337

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.
not provided	Pathogenic (1)	criteria provided, single submitter	-	RCV002280087.2
Cowden syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 29, 2022	RCV003096320.3
PIK3CA related overgrowth syndrome	Likely pathogenic (1)	criteria provided, single submitter	Oct 18, 2023	RCV003458242.1

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.	More information 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.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV002568862.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022
Likely pathogenic (Oct 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PIK3CA-related overgrowth syndrome Affected status: yes Allele origin: somatic	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176939.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: The PIK3CA c.344G>T (p.Arg115Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in twelve cases in the … (more) The PIK3CA c.344G>T (p.Arg115Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in twelve cases in the cancer database COSMIC (COSMIC ID: COSV55890007) and is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies show that the c.344G>T (p.Arg115Leu) variant confers a gain of function to the Pik3ca protein as demonstrated by increased cell growth, activation of the PI3K pathway (Lui VW et al., PMID: 23619167) and increased transformation ability in two different cell lines, as compared to wild-type Pik3ca (Ng PK et al., PMID: 29533785). Another variant in the same codon, (p.Arg115Pro), has been reported in an individual with macrodactyly and was considered pathogenic (Rios JJ et al., PMID: 23100325). The PIK3CA gene is defined by the ClinGen Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al. PMID: 35997716). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.344G>T (p.Arg115Leu) variant is classified as likely pathogenic. (less)
Uncertain significance (Jul 29, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cowden syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003224758.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 23754335‚ 23100325 Comment: 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 … (more) 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. This variant disrupts the p.Arg115 amino acid residue in PIK3CA. Other variant(s) that disrupt this residue have been observed in individuals with PIK3CA-related conditions (PMID: 23754335), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with macrodactyly (PMID: 23100325). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 115 of the PIK3CA protein (p.Arg115Leu). (less)

Comment:

The PIK3CA c.344G>T (p.Arg115Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in twelve cases in the cancer database COSMIC (COSMIC ID: COSV55890007) and is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies show that the c.344G>T (p.Arg115Leu) variant confers a gain of function to the Pik3ca protein as demonstrated by increased cell growth, activation of the PI3K pathway (Lui VW et al., PMID: 23619167) and increased transformation ability in two different cell lines, as compared to wild-type Pik3ca (Ng PK et al., PMID: 29533785). Another variant in the same codon, (p.Arg115Pro), has been reported in an individual with macrodactyly and was considered pathogenic (Rios JJ et al., PMID: 23100325). The PIK3CA gene is defined by the ClinGen Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al. PMID: 35997716). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.344G>T (p.Arg115Leu) variant is classified as likely pathogenic.

Comment:

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. This variant disrupts the p.Arg115 amino acid residue in PIK3CA. Other variant(s) that disrupt this residue have been observed in individuals with PIK3CA-related conditions (PMID: 23754335), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with macrodactyly (PMID: 23100325). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 115 of the PIK3CA protein (p.Arg115Leu).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Expanding the differential diagnosis of fetal hydrops: an unusual prenatal presentation of megalencephaly-capillary malformation syndrome.	Swarr DT	Prenatal diagnosis	2013	PMID: 23754335
Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly.	Rios JJ	Human molecular genetics	2013	PMID: 23100325

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_006218.4(PIK3CA):c.344G>T (p.Arg115Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...