rs786204875

Positions:

• chr10-87960913-G-A
• chr10-87960913-G-C
• chr10-87960913-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000314.8(PTEN):​c.821G>A​(p.Trp274Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.56

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87960913-G-A is Pathogenic according to our data. Variant chr10-87960913-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1762511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87960913-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.821G>A	p.Trp274Ter	stop_gained	8/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1340G>A	p.Trp447Ter	stop_gained	9/10		NP_001291646.4
PTEN	NM_001304718.2	c.230G>A	p.Trp77Ter	stop_gained	8/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.821G>A	p.Trp274Ter	stop_gained	8/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2024

The PTEN c.821G>A variant is predicted to result in premature protein termination (p.Trp274*). This variant was apparently detected and de novo in an individual with PTEN-related phenotypes (Busa et al 2015. PubMed ID: 25549896, reported with a protein nomenclature error, NM_000314:c.821G>A, p.Thr274X). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in PTEN, are expected to be pathogenic, and several have been associated with disease immediately up- and downstream of this variant position. This variant is interpreted as pathogenic. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1762511). This premature translational stop signal has been observed in individual(s) with PTEN hamartoma tumor syndrome (PMID: 21659347, 25549896). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp274*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2021

The p.W274* pathogenic mutation (also known as c.821G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 821. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This mutation reportedly occurred de novo in a patient diagnosed in early childhood with developmental delay, motor and speech delay, macrocephaly, and abnormal brain MRI (Busa T et al. Eur. J. Paediatr. Neurol. 2015 Mar;19:188-92). This mutation was also reported in an individual with features of PTEN hamartoma tumor syndrome (Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12) including macrocephaly, skin papules, a neurofibroma, a mucosal neuroma, and cafe au lait spots at age 13 (Pilarski R, personal communication). Of note, this alteration is also designated as p.Thr274X in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	54
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A
Vest4		0.94
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204875; hg19: chr10-89720670; COSMIC: COSV64288869;