chr10-87931033-ACTTTT-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS3BS1

This summary comes from the ClinGen Evidence Repository: PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) LINK:https://erepo.genome.network/evrepo/ui/classification/CA059460/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 2 hom. )

Consequence

PTEN
NM_000314.8 splice_region, intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel P:1U:5B:18

Conservation

PhyloP100: 3.82

Publications

3 publications found

Variant links:

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN Gene-Disease associations (from GenCC):

Cowden syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
PTEN hamartoma tumor syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
macrocephaly-autism syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
leiomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
activated PI3K-delta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bannayan-Riley-Ruvalcaba syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lhermitte-Duclos disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Proteus-like syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
glioma susceptibility 2
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PTEN links:

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ACMG classification

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

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PTEN	NM_000314.8	MANE Select	c.210-7_210-3delCTTTT	splice_region intron	N/A	NP_000305.3
PTEN	NM_001304717.5		c.729-7_729-3delCTTTT	splice_region intron	N/A	NP_001291646.4
PTEN	NM_001304718.2		c.-541-7_-541-3delCTTTT	splice_region intron	N/A	NP_001291647.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PTEN	ENST00000371953.8	TSL:1 MANE Select	c.210-12_210-8delCTTTT	splice_region intron	N/A	ENSP00000361021.3	P60484-1
PTEN	ENST00000693560.1		c.729-12_729-8delCTTTT	splice_region intron	N/A	ENSP00000509861.1	A0A8I5KSF9
PTEN	ENST00000700029.2		c.210-12_210-8delCTTTT	splice_region intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

151628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000296

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000289

AC:

AN:

249456

AF XY:

0.000230

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00140

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000302

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000429

AC:

621

AN:

1446668

Hom.:

AF XY:

0.000391

AC XY:

282

AN XY:

720342

show subpopulations

African (AFR)

AF:

0.0000907

AC:

AN:

33078

American (AMR)

AF:

0.000225

AC:

AN:

44534

Ashkenazi Jewish (ASJ)

AF:

0.000927

AC:

AN:

25880

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39362

South Asian (SAS)

AF:

0.000128

AC:

AN:

85850

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.000880

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.000478

AC:

526

AN:

1099268

Other (OTH)

AF:

0.000652

AC:

AN:

59796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000237

AC:

AN:

151746

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41528

American (AMR)

AF:

0.000132

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000296

AC:

AN:

67660

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000781

Hom.:

Bravo

AF:

0.000321

Asia WGS

AF:

0.000290

AC:

AN:

3464

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

PTEN hamartoma tumor syndrome (5)

Cowden syndrome 1 (3)

Hereditary cancer-predisposing syndrome (3)

Breast and/or ovarian cancer (1)

Familial cancer of breast (1)

PTEN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over