10-87965473-AT-ATT

Position:

• chr10-87965473-AT-ATT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000314.8(PTEN):​c.*10dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 151,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.10

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-87965473-A-AT is Benign according to our data. Variant chr10-87965473-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.*10dupT		3_prime_UTR_variant	9/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.*10dupT		3_prime_UTR_variant	10/10		NP_001291646.4
PTEN	NM_001304718.2	c.*10dupT		3_prime_UTR_variant	9/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.*10dupT		3_prime_UTR_variant	9/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151598 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000433 AC: 63 AN: 1455874 Hom.: 0 Cov.: 33 AF XY: 0.0000428 AC XY: 31 AN XY: 724112

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.0000680

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000289

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151714 Hom.: 0 Cov.: 31 AF XY: 0.0000675 AC XY: 5 AN XY: 74128

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cowden syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 10, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs756681683; hg19: chr10-89725230;