VCV000045464.10 - ClinVar

NM_006218.4(PIK3CA):c.1252G>A (p.Glu418Lys)

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.

(4)

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); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.

Likely oncogenic

criteria provided, single submitter

Variant Details

Identifiers

NM_006218.4(PIK3CA):c.1252G>A (p.Glu418Lys)

Variation ID: 45464 Accession: VCV000045464.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179210186 (GRCh38) [ NCBI UCSC ] 3: 178927974 (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	Jan 31, 2015	Oct 8, 2024	Oct 10, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.1252G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Glu418Lys	missense
NC_000003.12:g.179210186G>A
NC_000003.11:g.178927974G>A
NG_012113.2:g.66664G>A
LRG_310:g.66664G>A
LRG_310t1:c.1252G>A

... more HGVS ... less HGVS

Protein change

E418K

Other names

Canonical SPDI

NC_000003.12:179210185:G:A

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

gain_of_function_variant; Sequence Ontology [ SO:0002053]

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

ClinGen: CA136365 dbSNP: rs397517199 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	1298	1332

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 specified	Uncertain significance (1)	criteria provided, single submitter	Nov 19, 2012	RCV000038669.5
CLOVES syndrome	Likely pathogenic (1)	no assertion criteria provided	-	RCV001256198.2
PIK3CA related overgrowth syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 10, 2023	RCV003458192.1
PIK3CA-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jan 31, 2024	RCV004534818.3

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 (Oct 10, 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: SCV004176924.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: The PIK3CA c.1252G>A (p.Glu418Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-related … (more) The PIK3CA c.1252G>A (p.Glu418Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-related overgrowth spectrum (PROS) disorders (Kuentz P et al., PMID: 28151489; Parker VER et al., PMID: 30270358; Gripp KW et al., PMID: 27191687). This variant has been reported in the ClinVar database as a likely pathogenic variant of somatic origin by one submitter and a variant of uncertain significance by one submitter (ClinVar ID: 45464 ) and has been reported in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV55880477). This variant is absent from the general population (gnomAD v3.1.2), indicating that it is not a common variant. The PIK3CA c.1252G>A (p.Glu418Lys) variant resides within a C2 domain, amino acids 325-484, of PIK3CA that is defined as a critical functional domain (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene is defined by the ClinGen's 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). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. 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.1252G>A (p.Glu418Lys) variant is classified as pathogenic. (less)
Uncertain significance (Nov 19, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Not Specified Affected status: not provided Allele origin: somatic	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062347.3 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Number of individuals with the variant: 1
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	CLOVES syndrome (Somatic mutation) Affected status: yes Allele origin: somatic	Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen Accession: SCV001429632.1 First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020	Clinical Features: Global developmental delay (present) , Lipomatous tumor (present) , 2-3 toe syndactyly (present) Age: 20-29 years Sex: male Comment on evidence: Variant found in affected tissue, variant absent in DNA from blood sample.
Likely pathogenic (Jan 31, 2024)	no assertion criteria provided Method: clinical testing	PIK3CA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004721553.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The PIK3CA c.1252G>A variant is predicted to result in the amino acid substitution p.Glu418Lys. This variant has been reported as a mosaic alteration in multiple … (more) The PIK3CA c.1252G>A variant is predicted to result in the amino acid substitution p.Glu418Lys. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Gripp et al. 2016. PubMed ID: 27191687; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, the p.Glu418Lys variant is located within a kinase domain (p.322-483) critical for p110α protein function, as evaluated by the ClinGen Brain Malformation Variant Curation Expert Panel (Table 3, Lai et al. 2022. PubMed ID: 35997716). Taken together, this variant is interpreted as likely pathogenic. (less)

Comment:

The PIK3CA c.1252G>A (p.Glu418Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-related overgrowth spectrum (PROS) disorders (Kuentz P et al., PMID: 28151489; Parker VER et al., PMID: 30270358; Gripp KW et al., PMID: 27191687). This variant has been reported in the ClinVar database as a likely pathogenic variant of somatic origin by one submitter and a variant of uncertain significance by one submitter (ClinVar ID: 45464 ) and has been reported in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV55880477). This variant is absent from the general population (gnomAD v3.1.2), indicating that it is not a common variant. The PIK3CA c.1252G>A (p.Glu418Lys) variant resides within a C2 domain, amino acids 325-484, of PIK3CA that is defined as a critical functional domain (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene is defined by the ClinGen's 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). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. 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.1252G>A (p.Glu418Lys) variant is classified as pathogenic.

Comment:

The PIK3CA c.1252G>A variant is predicted to result in the amino acid substitution p.Glu418Lys. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Gripp et al. 2016. PubMed ID: 27191687; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, the p.Glu418Lys variant is located within a kinase domain (p.322-483) critical for p110α protein function, as evaluated by the ClinGen Brain Malformation Variant Curation Expert Panel (Table 3, Lai et al. 2022. PubMed ID: 35997716). Taken together, this variant is interpreted as likely pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
gain_of_function_variant (SO:0002053)			Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen Accession: SCV001429632.1

Comment:

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.

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Likely oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668761.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Likely oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094529.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic 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 rs397517199 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_006218.4(PIK3CA):c.1252G>A (p.Glu418Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs397517199 ...