rs786204933

Positions:

• chr10-87933196-T-A
• chr10-87933196-T-G

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.437T>A​(p.Leu146Ter) variant causes a stop gained change involving the alteration of a non-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: 32)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.78

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 10-87933196-T-A is Pathogenic according to our data. Variant chr10-87933196-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 189488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.437T>A	p.Leu146Ter	stop_gained	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.956T>A	p.Leu319Ter	stop_gained	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-314T>A		5_prime_UTR_variant	4/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.437T>A	p.Leu146Ter	stop_gained	5/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2014

This mutation is denoted PTEN c.437T>A at the cDNA level and p.Leu14Ter (L146X) at the protein level. The substitution creates a nonsense variant, changing a Leucine to a premature stop codon (TTA>TAA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not been published as a germline pathogenic variant to our knowledge, it has been reported as a somatic mutation in association with endometrial cancer (Catasus 2008, Murayama-Hosokawa 2001). Exon 5 of the PTEN gene has been described as a mutational hot-spot, and, in one study, almost half of all Cowden syndrome-associated PTEN mutations were identified in this exon (Marsh 1998). Based on current information, we consider this variant to be pathogenic. The PTEN hamartoma tumor syndrome (PHTS) conditions associated with cancer risk include Cowden Syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRRS). The cancer risks include approximately 25-45% risk for breast cancer in women, 5-10% risk for endometrial cancer in women, and 10% risk for non-medullary thyroid cancer in men and women (Hobert 2009). In addition to the cancer risks, these autosomal dominant conditions include other distinct features. Individuals with CS typically have one or more features including an increased head circumference in at least the 97th percentile (macrocephaly), trichilemmomas, papillomatous papules, and the pathognomonic finding of cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease). BRRS is associated with macrocephaly, intestinal hamartomas, pigmented macules of the glans penis, and can be associated with developmental delay or autism. CS is also associated with benign conditions including benign breast disease, thyroid goiters, benign gastrointestinal polyps, and uterine fibroids. Vascular abnormalities, such as hemangiomas and arteriovenous malformations have also been reported individuals with PTEN mutations. Of note, a recent prospective study of individuals with germline PTEN mutations has suggested that the cancer risks may be higher than previously reported as well as expanding the cancer spectrum to include increased risks for colorectal cancer, kidney cancer, and melanoma (Tan 2012). Male breast cancer has also been reported in patients with a PTEN mutation (Fackenthal 2001). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2016

The p.L146* pathogenic mutation (also known as c.437T>A), located in coding exon 5 of the PTEN gene, results from a T to A substitution at nucleotide position 437. This changes the amino acid from a leucine to a stop codon within coding exon 5. 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	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	A
Vest4		0.99
GERP RS		5.2

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: rs786204933; hg19: chr10-89692953; COSMIC: COSV64294541;