rs121909232

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_000314.8(PTEN):c.633C>A(p.Cys211*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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, splice_region

Scores

Splicing: ADA: 0.9741

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.72

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 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;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 10-87952258-C-A is Pathogenic according to our data. Variant chr10-87952258-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87952258-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.633C>A	p.Cys211*	stop_gained, splice_region_variant	Exon 6 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.1152C>A	p.Cys384*	stop_gained, splice_region_variant	Exon 7 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.42C>A	p.Cys14*	stop_gained, splice_region_variant	Exon 6 of 9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.633C>A	p.Cys211*	stop_gained, splice_region_variant	Exon 6 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249014

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726422

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jun 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history consistent with pathogenic variants in PTEN (Wanner et al., 2001; Zhou et al., 2001; Kim et al., 2005; Sarquis et al., 2006; Ngeow et al., 2011; Pilarski et al., 2011; Ha et al., 2012; Ngeow et al., 2014); 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: 29785012, 16773562, 22371648, 21956414, 24778394, 21659347, 11476841, 11174374, 10978354, 16007494, 25525159, 9467011, 33726816, 30720243, 21194675) -

Oct 21, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cowden syndrome 1

Pathogenic:2

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Jun 14, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTEN hamartoma tumor syndrome

Pathogenic:2

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS), collectively also known as PTEN hamartoma tumor syndrome (PMID: 11476841, 16007494, 16773562, 21659347, 21956414, 22371648, 24778394). This variant is present in population databases (rs121909232, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Cys211*) 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). ClinVar contains an entry for this variant (Variation ID: 7836). For these reasons, this variant has been classified as Pathogenic. -

PTEN-related disorder

Pathogenic:1

Mar 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTEN c.633C>A variant is predicted to result in premature protein termination (p.Cys211*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome with both inherited and de novo cases reported (Table 1, Zhou et al 2001. PubMed ID: 11476841; Figure 1, Wanner et al. 2001. PubMed ID: 11174374; Table 1, Sarquis et al. 2006. PubMed ID: 16773562). This variant is reported in 1 of ~249,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-89712015-C-A) and is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/7836/). Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Melanoma

Pathogenic:1

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jul 27, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C211* pathogenic mutation (also known as c.633C>A), located in coding exon 6 of the PTEN gene, results from a C to A substitution at nucleotide position 633. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with a PTEN-related disorder (Zhou XP et al. Lancet. 2011;358(9277):210-1; Pilarski R et al. J Med Genet. 2011;48(8):505-12; Ngeow, J et al. J Clin Oncol. 2014 Jun 10;32(17):1818-24). 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

0.51

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.95

Vest4

0.98

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over