10-87961095-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000314.8(PTEN):c.1003C>T(p.Arg335*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,168 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 (★★).
Frequency
Consequence
NM_000314.8 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.1003C>T | p.Arg335* | stop_gained | Exon 8 of 9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304717.5 | c.1522C>T | p.Arg508* | stop_gained | Exon 9 of 10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.412C>T | p.Arg138* | stop_gained | Exon 8 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461168Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 726936
GnomAD4 genome
ClinVar
Submissions by phenotype
Cowden syndrome 1 Pathogenic:8Uncertain:1Other:1
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The c.1003C>T;p.(Arg335*) variant creates a premature translational stop signal in the PTEN gene. It is expected to result in an absent or disrupted protein product -PVS1. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 10749983, 10232405) - PS2. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 7833 ; PMID: 20301661; 33600059; 22595938) - PS4. This variant is not present in population databases (rs121909231- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
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Recurrent pathogenic variants -
A PTEN c.1003C>T (p.Arg335*) variant was identified at a near heterozygous allelic fraction, a frequency which may be consistent with germline origin. This variant has been reported in several individuals with PTEN hamartoma tumor syndrome (PHTS) in both a de novo and inherited fashion (Cavaillé M et al., PMID: 30233642; Wong CW et al., PMID: 29608813; Taylor A et al., PMID: 25756585; Celebi JT et al., PMID: 10353779; Soysal Y et al., PMID: 24052722; Busa T et al., PMID: 25549896). It has been reported in the ClinVar database as a germline pathogenic variant by multiple submitters (ClinVar ID: 7833). The PTEN c.1003C>T (p.Arg335*) variant is only observed on 2/1,613,254 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant. This single nucleotide variant leads to a premature termination codon; however, because this occurs in the penultimate exon, this is not predicted to lead to nonsense mediated decay. Functional studies show decreased protein expression and stability and increased pAKT and pERK signaling (He X et al., PMID: 23475934). Based on the available information, the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and the ClinGen PTEN expert panel (Mester JL et al., PMID: 30311380), this variant is classified as pathogenic. -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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PM2_Supporting+PVS1+PS4+PM6_VeryStrong -
not provided Pathogenic:7
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Published functional studies demonstrate a damaging effect: decreased protein expression and stability, increased pAKT and pERK signaling (He et al., 2013); Nonsense variant in the C-terminus predicted to result in protein truncation as the last 69 amino acids are lost, disrupting the critical C2 domain (Wang et al., 2008); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25344691, 14518070, 16410744, 21798893, 22675565, 24778394, 23619167, 23695273, 22381246, 29608813, 28475857, 33600059, 10749983, 25756585, 11875759, 10353779, 11685670, 10848731, 21956414, 17392703, 15633233, 16618716, 17515920, 18772396, 23917401, 11555573, 10092130, 27165089, 27563534, 27797976, 17526801, 25549896, 23470840, 9399897, 23475934, 25288137, 27959697, 28724667, 29909963, 28526761, 22595938, 28152038, 31086789, 30233642, 31023376, 30426508, 30528446, 18626510, 23335809, 32238909, 31447099, 32581362, 33509259, 31594918, 33077954) -
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PTEN: PVS1, PS2, PM2, PS4:Moderate, PS3:Supporting -
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PTEN hamartoma tumor syndrome Pathogenic:4
This sequence change creates a premature translational stop signal (p.Arg335*) in the PTEN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the PTEN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hamartoma tumor syndrome (PMID: 9399897, 9467011, 10232405, 10353779, 10400993, 10749983, 11685670, 24052722). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7833). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PTEN function (PMID: 9399897, 23475934). For these reasons, this variant has been classified as Pathogenic. -
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proposed classification - variant undergoing re-assessment, contact laboratory -
This variant changes 1 nucleotide in exon 8 of the PTEN gene, creating a premature translation stop signal in the penultimate exon. A functional study has shown that the variant causes decrease in PTEN RNA transcript and protein expression (PMID: 23475934). This variant has been reported in individuals affected with PTEN hamartoma tumor syndrome (PMID: 9467011, 10232405, 10353779, 10400993, 10848731, 11685670, 11918710, 11685670, 18558293, 22595938, 23475934, 23695273, 23934601, 24052722, 24778394, 25549896, 27477328, 28526761) and has been shown to segregate with disease in at least two of the families (PMID: 10353779, 11685670). This variant has also been reported to arise de novo in some of these individuals (PMID: 22595938, 24052722, 25549896, 28526761). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:4
The p.R335* pathogenic mutation (also known as c.1003C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide position 1003. This changes the amino acid from an arginine to a stop codon within coding exon 8. This alteration occurs at the 3' terminus of thePTEN gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 69 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in several individuals and/or families with clinical manifestations of the PTEN hamartoma tumor syndrome (PHTS) including Cowden or Cowden-like syndrome (Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec;96:E2063-71; Lynch ED et al. Am. J. Hum. Genet. 1997 Dec;61:1254-60; Mester JL et al. Urology. 2012 May;79:1187.e1-7; Busch RM et al. Genet. Med. 2013 Jul;15:548-53; Kubo Y et al. Br. J. Dermatol. 2000 Jun;142:1100-5; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Whitworth J et al. Am. J. Hum. Genet. 2018 Jul;103(1):3-18), Proteus-like syndrome (Zhou XP et al. Hum. Mol. Genet. 2000 Mar;9:765-8), and Bannayan-Riley-Ruvalcaba syndrome (Tok Celebi J et al. Exp. Dermatol. 1999 Apr;8:134-9; Hobert JA et al. Eur. J. Hum. Genet. 2014 Feb;22:273-6; Posey JE et al. N. Engl. J. Med. 2017 01;376(1):21-31). In an in vitro study, this alteration was shown to significantly reduce protein expression and significantly elevate proteasome activity. The authors suggested that patients with mutations causing elevated proteasome activity could have more neurological manifestations than those with mutations that do not lead to elevated activity (He X et al. Cancer Res. 2013 May;73:3029-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
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This variant changes 1 nucleotide in exon 8 of the PTEN gene, creating a premature translation stop signal in the penultimate exon. A functional study has shown that the variant causes decrease in PTEN RNA transcript and protein expression (PMID: 23475934). This variant has been reported in individuals affected with PTEN hamartoma tumor syndrome (PMID: 9467011, 10232405, 10353779, 10400993, 10848731, 11685670, 11918710, 11685670, 18558293, 22595938, 23475934, 23695273, 23934601, 24052722, 24778394, 25549896, 27477328, 28526761) and has been shown to segregate with disease in at least two of the families (PMID: 10353779, 11685670). This variant has also been reported to arise de novo in some of these individuals (PMID: 22595938, 24052722, 25549896, 28526761). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Macrocephaly-autism syndrome Pathogenic:3
Our laboratory reported dual molecular diagnoses in DNM1 (NM_001005336.1, c.465_467dup) and PTEN (NM_000314.4, c.1003C>T) in one individual with reported features of global developmental delay with concern for regression, speech delay, hypotonia, macrocephaly, seizure disorder, swallowing difficulty. The PTEN variant has been previously reported as disease causing [PMID 9399897, 21956414, 10749983]. Additionally, this variant was found once in our laboratory maternally inherited in a 6-year-old female with hypotonia, chronic lung disease, macrocephaly, polydatyly, atrial septal defect, dysautonomia. -
PVS1, PS2, PS4, PM2 -
ACMG evidence PVS1, PS2, PM2 -
PTEN-related disorder Pathogenic:2
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The PTEN c.1003C>T variant is predicted to result in premature protein termination (p.Arg335*). This variant has been reported to be causative for Cowden syndrome, and has been observed to arise de novo in some individuals and as an inherited variant in others (See for example: referred to as 1003C>T, R334X, Lynch et al. 1997. PubMed ID: 9399897; Table S1, Busch et al. 2013. PubMed ID: 23470840; Ngeow et al. 2014. PubMed ID: 24778394; Benson et al. 2020. PubMed ID: 32238909). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic by several laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7833/). Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic. -
Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Pathogenic:1
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Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1 Pathogenic:1
This variant has been previously reported as disease-causing and was found twice in our laboratory: de novo in a 2-year-old female with global delays, hypotonia, macrocephaly, epilepsy, swallowing difficulty, abnormal muscle fibers; maternally inherited in a 6-year-old female with hypotonia, sleep apnea, GERD, chronic lung disease, laryngomaliacia, macrocephaly, polydactyly, atrial septal defect, decreased hearing, possible dysautonomia -
Familial cancer of breast Pathogenic:1
The PTEN c.1003C>T variant is classified as Pathogenic (PVS1, PM2, PP1_Strong) -
Cowden syndrome Pathogenic:1
Variant summary: PTEN c.1003C>T (p.Arg335X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250932 control chromosomes. c.1003C>T has been frequently reported in the literature in multiple individuals affected with Cowden Syndrome, breast cancer and overlapping features of PTEN Hamartoma Tumor Syndromes (example, Lynch_1997, Nizialek_2015, Momozawa_2018, Celebi_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of mutant transcripts consistent with degradation of these transcripts through a nonsense-mediated pathway and loss of heterozygosity in tumors (Lynch_1997). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Ovarian neoplasm Pathogenic:1
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Proteus-like syndrome Pathogenic:1
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Abnormality of the nervous system Pathogenic:1
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Neoplasm Other:1
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Cowden syndrome;C1854416:Macrocephaly-autism syndrome Other:1
Variant interpreted as Pathogenic and reported on 01-25-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at