rs557364463

chr10-87960840-ATTAATTAAATATGTCATTTCATTTCTTTTTCTTTTCTT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000314.8(PTEN):c.802-51_802-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 151,260 control chromosomes in the GnomAD database, including 91 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.018 (91 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: 1.40

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 10-87960840-ATTAATTAAATATGTCATTTCATTTCTTTTTCTTTTCTT-A is Benign according to our data. Variant chr10-87960840-ATTAATTAAATATGTCATTTCATTTCTTTTTCTTTTCTT-A is described in ClinVar as [Benign]. Clinvar id is 220416.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87960840-ATTAATTAAATATGTCATTTCATTTCTTTTTCTTTTCTT-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.802-51_802-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371953.8
PTEN	NM_001304717.5	c.1321-51_1321-14del		splice_polypyrimidine_tract_variant, intron_variant
PTEN	NM_001304718.2	c.212-51_212-14del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.802-51_802-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2758 AN: 151158 Hom.: 90 Cov.: 31

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0139

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00166 AC: 2244 AN: 1354456 Hom.: 6 AF XY: 0.00145 AC XY: 971 AN XY: 670666

Gnomad4 AFR exome AF: 0.0626

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000685

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000607

Gnomad4 OTH exome AF: 0.00387

GnomAD4 genome AF: 0.0182 AC: 2757 AN: 151260 Hom.: 91 Cov.: 31 AF XY: 0.0173 AC XY: 1282 AN XY: 73914

Gnomad4 AFR AF: 0.0625

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.0129 Hom.: 5

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 23, 2019	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 20, 2020	- -

PTEN hamartoma tumor syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	- -
Benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Mar 23, 2020	PTEN c.802-51_802-14del (IVS7-51_IVS7-14del) 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). BA1: Allele frequency of 0.01931 (1.931%, 2747/142,290 alleles) in the global gnomAD cohort. (PMID 27535533) -

not provided Benign:2

Benign, flagged submission	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 11986403) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2018	- -

Cowden syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

May 26, 2017

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs557364463; hg19: chr10-89720597;