rs886047384

Positions:

• chr10-87863735-G-A
• chr10-87863735-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.-735G>A meets criteria to be classified as likely benign 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).BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF in gnomAD for South Asians: 0.01758%.Per ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3, 1 Benign Strong = Likely Benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10602385/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PTEN NM_000314.8 5_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:3
• Conservation: PhyloP100: 0.933

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.-735G>A		5_prime_UTR_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.-215G>A		5_prime_UTR_variant	1/10		NP_001291646.4
PTEN	NM_001304718.2	c.-1440G>A		5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953	c.-735G>A		5_prime_UTR_variant	1/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.0000203 AC: 3 AN: 147774 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000646

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000167 AC: 4 AN: 239478 Hom.: 0 Cov.: 0 AF XY: 0.0000164 AC XY: 2 AN XY: 121742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000633

GnomAD4 genome AF: 0.0000203 AC: 3 AN: 147774 Hom.: 0 Cov.: 32 AF XY: 0.0000415 AC XY: 3 AN XY: 72212

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000646

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2015	This variant is denoted PTEN c.-735G>A, and describes a nucleotide substitution 735 base pairs upstream of the ATG translational start site in the PTEN promoter region. The surrounding sequence, with the base that is substituted in brackets, is GCCC[G/A]GAGC. This variant, also called c.-734G>A using alternate numbering, has not been published in the literature to our knowledge. One study found that approximately 9% (9/95) of patients with Cowden syndrome (CS) were identified to have a point variant in the PTEN core promoter region (c.-798 to c.-1238) (Zhou 2003). While the c.-735G>A variant is outside of this core promoter region, it could still have an effect on transcription and, possibly, PTEN protein levels. Based on the currently available information, we consider this to be a variant of uncertain significance. -

PTEN hamartoma tumor syndrome Uncertain:1 Benign:1

Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Aug 04, 2023	NM_000314.8(PTEN):c.-735G>A meets criteria to be classified as likely benign 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). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF in gnomAD for South Asians: 0.01758%. Per ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3, 1 Benign Strong = Likely Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 09, 2023

- -

PTEN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cowden syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Feb 06, 2018

Research exome identified causative de novo mutation in PPP2R5D that explains proband's phenotype reducing the likelihood the PTEN c.-734G>A is associated with disease. The mother of the observed proband also carries variant and does not have features of PHTS/Cowden's syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886047384; hg19: chr10-89623492;