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NM_000314.8(PTEN):c.209+5G>A AND not provided

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Nov 17, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001358192.4

Allele description [Variation Report for NM_000314.8(PTEN):c.209+5G>A]

NM_000314.8(PTEN):c.209+5G>A

Gene:
PTEN:phosphatase and tensin homolog [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q23.31
Genomic location:
Preferred name:
NM_000314.8(PTEN):c.209+5G>A
HGVS:
  • NC_000010.11:g.87925562G>A
  • NG_007466.2:g.67124G>A
  • NM_000314.8:c.209+5G>AMANE SELECT
  • NM_001304717.5:c.729+5G>A
  • NM_001304718.2:c.-541-5484G>A
  • LRG_311t1:c.209+5G>A
  • LRG_311:g.67124G>A
  • NC_000010.10:g.89685319G>A
  • NM_000314.4:c.209+5G>A
  • NM_000314.6:c.209+5G>A
Links:
dbSNP: rs1114167650
NCBI 1000 Genomes Browser:
rs1114167650
Molecular consequence:
  • NM_000314.8:c.209+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001304717.5:c.729+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001304718.2:c.-541-5484G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001553865Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Pathogenicunknownclinical testing

SCV002512883GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Pathogenic
(Nov 17, 2020) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553865.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The PTEN c.209+5G>A variant was identified in 6 of 238 proband chromosomes (frequency: 0.0252) from individuals or families with Cowden syndrome and Bannayan–Zonana syndrome (Celebi_1999, Chen_2017, Marsh_1998, Plamper_2017). The variant was also identified in dbSNP (ID: rs1114167650) as “With Pathogenic allele”, ClinVar (as pathogenic by Ambry Genetics and Cleveland Clinic), Clinvitae (2x as in ClinVar), Cosmic (found as a somatic mutation 3 x in the central nervous system, 2 x in the endometrium, 1 x in the lung and 1 x in the kidney), LOVD 3.0 (2x as pathogenic), and Zhejiang Colon Cancer Database (1 x). The variant was not identified in the MutDB database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). A functional study showed the c.209+5G>A variant led to the splicing out of exon 3 in two different patients affected with Cowden syndrome (Agrawal_2005). A microarray study of gene expression analysis in 74 tumours from patients with familial breast cancer found the variant in 4 tumours (Banneau_2010). The variant has also been reported in adolescents with PTEN hamartoma tumour syndrome (Plamper_2017) and in a patient with glioblastoma (Rickert_2009). The c.209+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV002512883.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Intronic +5 splice site variant demonstrated to result in an in-frame deletion of exon 3, disrupting the critical phosphatase domain and ATP binding motifs (Agarwal 2005, Lobo 2009, Molinari 2014, Chen 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22595938, 10340391, 23695273, 25525159, 31336731, 31784482, 16014636, 18626099, 11071384, 28315423, 32959437, 10232405, 9467011, 20712882, 23335809, 28677221, 19457929, 24475377, 32885271)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024