rs138336847

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PM6_StrongPM2_SupportingPS3

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.634+5G>A meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6_S: one proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype (PMID:18080326). PS3: assay shows impact on splicing. (PMID:18080326).PM2_P: Absent in large sequenced populations (gnomAD). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603167/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PTEN
NM_000314.8 splice_donor_5th_base, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 9.46

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 9 ACMG points.

PS3

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

PM2

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

PM6

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
PTEN	NM_000314.8 linkuse as main transcript	c.634+5G>A	splice_donor_5th_base_variant, intron_variant	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1153+5G>A	splice_donor_5th_base_variant, intron_variant		NP_001291646.4
PTEN	NM_001304718.2 linkuse as main transcript	c.44+5G>A	splice_donor_5th_base_variant, intron_variant		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.634+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000314.8	ENSP00000361021	P1	P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248530

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134556

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459564

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Dec 01, 2023	NM_000314.8(PTEN):c.634+5G>A meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM6_S: one proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype (PMID:18080326). PS3: assay shows impact on splicing. (PMID:18080326). PM2_P: Absent in large sequenced populations (gnomAD). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 280031). This variant has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 11332402, 17526800, 18080326). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs138336847, gnomAD 0.003%). This sequence change falls in intron 6 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein. It affects a nucleotide within the consensus splice site. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2022

Published functional studies demonstrate a damaging effect: skipping of exon 6 in patient RNA (Boccone et al., 2008); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15169818, 11332402, 17526800, 18080326, 21291452, 30720243) -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 10, 2022

- -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2021

The c.634+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 6 in the PTEN gene. This mutation has been identified in multiple individuals with PTEN hamartoma tumor syndrome (PHTS) (Parisi MA et al. J. Med. Genet., 2001 Jan;38:52-8; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Boccone L et al. Am. J. Med. Genet. A, 2008 Jan;146A:257-60; Kersseboom R et al. Clin. Genet., 2012 Jun;81:555-62). This alteration is also identified as a de novo mutation in a six-year-old male diagnosed with extreme macrocephaly, lipoma, penile freckling and autism, and in an 11-year-old male diagnosed with macrocephaly, goitre, lipoma, oral papilloma, haemangioma and gastrointestinal polyps (Boccone L et al. Am. J. Med. Genet. A, 2008 Jan;146A:257-60; Kersseboom R et al. Clin. Genet., 2012 Jun;81:555-62). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Boccone L et al. Am. J. Med. Genet. A, 2008 Jan;146A:257-60; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.97

Position offset: -5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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