rs121909232

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

4
2
1
Splicing: ADA: 0.9741
2

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 10-87952258-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
PTENNM_000314.8 linkc.633C>A p.Cys211* stop_gained, splice_region_variant Exon 6 of 9 ENST00000371953.8 NP_000305.3
PTENNM_001304717.5 linkc.1152C>A p.Cys384* stop_gained, splice_region_variant Exon 7 of 10 NP_001291646.4 P60484
PTENNM_001304718.2 linkc.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
PTENENST00000371953.8 linkc.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.:
32
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
249014
Hom.:
0
AF XY:
0.00
AC XY:
0
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:
1
AN:
1460034
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
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.:
32

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
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. -

May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
40
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Uncertain
0.95
D
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.

Other links and lift over

dbSNP: rs121909232; hg19: chr10-89712015; COSMIC: COSV64294019; API