10-87960876-CTTTTTTTTT-CTTTTTTTTTTTT

Position:

• chr10-87960876-CTTTTTTTTT-CTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The NM_000314.8(PTEN):​c.802-5_802-3dupTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,424,064 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (8 hom., cov: 26)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.37

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.18481848 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 10-87960876-C-CTTT is Benign according to our data. Variant chr10-87960876-C-CTTT is described in ClinVar as [Likely_benign]. Clinvar id is 802611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00751 (940/125116) while in subpopulation AFR AF= 0.0279 (886/31784). AF 95% confidence interval is 0.0264. There are 8 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.802-5_802-3dupTTT		splice_acceptor_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-5_1321-3dupTTT		splice_acceptor_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.211-5_211-3dupTTT		splice_acceptor_variant, intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-5_802-3dupTTT		splice_acceptor_variant, intron_variant		1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 937 AN: 125120 Hom.: 8 Cov.: 26

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0161

Gnomad NFE AF: 0.000238

Gnomad OTH AF: 0.00756

GnomAD4 exome AF: 0.000693 AC: 900 AN: 1298948 Hom.: 1 Cov.: 0 AF XY: 0.000680 AC XY: 440 AN XY: 646756

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000426

Gnomad4 EAS exome AF: 0.000533

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00751 AC: 940 AN: 125116 Hom.: 8 Cov.: 26 AF XY: 0.00705 AC XY: 426 AN XY: 60426

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.00169

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000248

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000238

Gnomad4 OTH AF: 0.00754

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2020	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 01, 2023

- -

PTEN hamartoma tumor syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2019

- -

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: rs34003473; hg19: chr10-89720633;