rs587781959

Positions:

• chr10-87863539-G-A
• chr10-87863539-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.-930G>A (NC_000010.10:g.89623296G>A) is currently classified as a variant of uncertain significance 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).PM2: Absent in large sequenced populations LINK:https://erepo.genome.network/evrepo/ui/classification/CA000640/MONDO:0017623/003

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN ENST00000693560 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:1
• Conservation: PhyloP100: 2.31

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]

(HGNC:):

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

ENSG00000289051 (HGNC:55481):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.87863539G>A		intergenic_region
KLLN	NM_001126049.2	c.-1052C>T		upstream_gene_variant		ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000693560	c.-411G>A		5_prime_UTR_variant	1/10			ENSP00000509861.1
PTEN	ENST00000688308.1	c.-17+426G>A		intron_variant				ENSP00000508752.1
KLLN	ENST00000445946.5	c.-1052C>T		upstream_gene_variant		6	NM_001126049.2	ENSP00000392204.2
ENSG00000289051	ENST00000692337.1	c.-20G>A		upstream_gene_variant				ENSP00000509326.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 233488 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 118760

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Oct 20, 2020

PTEN c.-930G>A (NC_000010.10:g.89623296G>A) is currently classified as a variant of uncertain significance 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). PM2: Absent in large sequenced populations -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 05, 2023

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with Cowden syndrome and thyroid cancer (PMID: 12844284 (2003)), and in an individual with thyroid cancer who did not meet clinical criteria for Cowden syndrome (PMID: 21417916 (2011)). Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2020

The c.-930G>A variant is located in the 5' untranslated region (5’ UTR) of the PTEN gene. This variant results from a G to A substitution 930 bases upstream from the first translated codon. This alteration was detected in a patient that was reported to have Cowden syndrome (CS), but clinical details were not provided and the alteration was predicted to alter a putative Sp1 transcription factor-binding site (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This variant was predicted to alter PTEN RNA structure by in silico analysis (Sabarinathan R et al. Hum. Mutat. 2013 Apr;34:546-56). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence for this variant is limited at this time, the clinical significance of this alteration remains unclear. -

Glioma susceptibility 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 18, 2024

- -

PTEN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.97

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: rs587781959; hg19: chr10-89623296;