rs121909227

Positions:

• chr10-87957858-C-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.640C>T​(p.Gln214Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.51

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 10-87957858-C-T is Pathogenic according to our data. Variant chr10-87957858-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7827.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.640C>T	p.Gln214Ter	stop_gained	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1159C>T	p.Gln387Ter	stop_gained	8/10		NP_001291646.4
PTEN	NM_001304718.2	c.49C>T	p.Gln17Ter	stop_gained	7/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.640C>T	p.Gln214Ter	stop_gained	7/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 29, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2023

This sequence change creates a premature translational stop signal (p.Gln214*) 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). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 7827). This premature translational stop signal has been observed in individual(s) with a diagnosis or suspicion of Cowden syndrome (PMID: 9832032, 10606430, 17954274, 21659347, 23160955, 27477328, 28086757). In at least one individual the variant was observed to be de novo. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27477328, 12560928, 9832032, 28086757, 21659347, 17954274, 10606430, 11918710, 27059323, 23160955, 24664487, 26197069, 21194675, 10232405, 28152038, 28191890, 34312540, 29752200, 35227301) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2019

The p.Q214* pathogenic mutation (also known as c.640C>T), located in coding exon 7 of the PTEN gene, results from a C to T substitution at nucleotide position 640. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration was confirmed as a de novo mutation in a patient meeting clinical criteria for Bannayan-Riley-Ruvalcaba (BRR) syndrome (Longy M et al. J. Med. Genet. 1998 Nov;35:886-9). This mutation has also been seen in multiple patients with Cowden syndrome (Bussaglia E et al. J. Invest. Dermatol. 2002 Apr;118:639-44; Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Kato K et al. Brain Dev. 2018 Sep;40(8):678-684) and in individuals with autism (O'Roak BJ et al. Science 2012 Dec;338:1619-22; Kosmicki J et al. Nat. Genet. 2017 Apr;49(4):504-510). Tate et al. report this mutation in an individual with hepatic angiosarcoma, breast and pharyngeal cancer, thyroid clear cell adenoma, and uterine leiomyoma (Tate G et al. Cancer Genet. Cytogenet. 2007 Oct;178:160-2). 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. -

Macrocephaly-autism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences

Nov 01, 2015

Patient, a 4 year-old girl, showed mild developmental delay and dysmorphic facial features. Her last head circumference was 57 cm (+4.1SD). The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A
Vest4		0.96
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 49

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909227; hg19: chr10-89717615; COSMIC: COSV64290622;