rs587782434
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS3BS1
This summary comes from the ClinGen Evidence Repository: PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) LINK:https://erepo.genome.network/evrepo/ui/classification/CA059460/MONDO:0017623/003
Frequency
Consequence
NM_000314.8 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.210-7_210-3del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000371953.8 | |||
PTEN | NM_001304717.5 | c.729-7_729-3del | splice_region_variant, intron_variant | ||||
PTEN | NM_001304718.2 | c.-540-7_-540-3del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.210-7_210-3del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000237 AC: 36AN: 151628Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000289 AC: 72AN: 249456Hom.: 0 AF XY: 0.000230 AC XY: 31AN XY: 134912
GnomAD4 exome AF: 0.000429 AC: 621AN: 1446668Hom.: 2 AF XY: 0.000391 AC XY: 282AN XY: 720342
GnomAD4 genome ? AF: 0.000237 AC: 36AN: 151746Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74168
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:1Uncertain:1Benign:3
Pathogenic, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Benign, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Mar 05, 2019 | PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). BS1: Allele frequency of 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Uncertain:1Benign:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 15, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 28, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 21, 2022 | Variant summary: PTEN c.210-7_210-3delCTTTT deletes 5 nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One publication reports experimental evidence that this variant affects mRNA splicing (Huang_2000), however, this effect was not confirmed in three other experimental studies (Brown_2000, Chen_2017, Casadei_2019), suggesting the variant does not significantly impact mRNA splicing. The variant allele was found at a frequency of 0.00029 in 249498 control chromosomes (gnomAD). The observed variant frequency is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Hereditary Breast And Ovarian Cancer Syndrome (1.6e-05), strongly suggesting that the variant is benign. c.210-7_210-3delCTTTT has been reported in the literature in individuals affected with different types of cancer without unequivocal conclusion. Fourteen ClinVar submitters, including one expert panel (ClinGen PTEN Variant Curation Expert Panel), have assessed the variant since 2014: one classified the variant as pathogenic, five as VUS, five as likely benign, and three (including the expert panel) as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Uncertain:1Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | PTEN: BP4 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2018 | This variant is associated with the following publications: (PMID: 21659347, 22995991, 11156385, 16287957, 28677221, 11120338) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PTEN c.210-7_210-3del variant was identified in 18 of 5644 proband chromosomes (frequency: 0.003) from individuals or families with endometrial cancer, Cowden syndrome, Li Fraumeni, and breast cancer (Black 2004, Brown 2000, Chen 2017 , Hobert 2012, Pilarski 2011, Sweet 2005, Tung 2015). The variant was also identified in dbSNP (ID: rs587780544) as “With other allele”, in ClinVar (with conflicting interpretations of pathogenicity; as likely benign by GeneDx, Invitae, and Integrated Genetics, and as uncertain significance by Ambry, Illumina, Counsyl, University of Chicago, Quest Diagnostics, EGL Genetic Diagnostics, and Cleveland Clinic), Cosmic (in endometrioid carcinoma), LOVD 3.0, and in the Zhejiang University Database (in individuals with Familial Juvenile Polyposis). The variant was not identified in the MutDB database. The variant was identified in control databases in 78 of 275204 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Ashkenazi Jewish in 16 of 10086 chromosomes (freq: 0.002), Other in 4 of 6406 chromosomes (freq: 0.0006), European (Non-Finnish) in 38 of 125410 chromosomes (freq: 0.0003), African in 7 of 23920 chromosomes (freq: 0.0003), Latino in 9 of 34240 chromosomes (freq: 0.0003), East Asian in 3 of 18782 chromosomes (freq: 0.0002), and South Asian in 1 of 30656 chromosomes (freq: 0.00003), while the variant was not observed in the Finnish population. The c.210-7_210-3del variant has inconsistent predictions of pathogenicity in the literature. Two functional studies of patients with Li-Fraumeni and Cowden syndrome showed the variant had no deleterious effect on mRNA processing (Brown 2000, Chen 2017). However, another study found an individual with the variant who met full Cowden syndrome diagnostic criteria exhibited elevated succinate in both plasma and urine, and concluded that the variant may actually be pathogenic (Hobert 2012). Another study of a family in which an unaffected father carried the variant, and his twin daughters both carried the variant and were affected with Juvenile Polyposis, concluded that RT-PCR analysis demonstrated the variant appears to affect RNA splicing (Huang 2000). The c.210-7_210-3del variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 06, 2023 | - - |
Cowden syndrome 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 23, 2015 | - - |
Uncertain significance, no assertion criteria provided | research | Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute | May 26, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2015 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 29, 2020 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 10, 2023 | - - |
PTEN-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 04, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 11, 2020 | The PTEN c.210-7_210-3del5 variant is classified as Benign (BS2, BP6_Strong) PTEN c.210-7_210-3del5 is located in intron 3. This variant has been observed in a healthy control population at a frequency which is inconsistent with expectations given the high penetrance of this condition under curation (BS2). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at