rs568851024
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1
This summary comes from the ClinGen Evidence Repository: PTEN c.579G>A (p.Leu193=) meets criteria to be classified as likely 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 0.00125 (0.125%, 13/10,360 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000523/MONDO:0017623/003
Frequency
Consequence
NM_000314.8 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.579G>A | p.Leu193= | synonymous_variant | 6/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.1098G>A | p.Leu366= | synonymous_variant | 7/10 | ||
PTEN | NM_001304718.2 | c.-13G>A | 5_prime_UTR_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.579G>A | p.Leu193= | synonymous_variant | 6/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000112 AC: 28AN: 251028Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135664
GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461438Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 727018
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74474
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Likely benign, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Nov 22, 2019 | PTEN c.579G>A (p.Leu193=) meets criteria to be classified as likely 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 0.00125 (0.125%, 13/10,360 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact. - |
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2014 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 26, 2023 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 12, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2015 | - - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 25, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2019 | - - |
Cowden syndrome 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Mar 22, 2018 | - - |
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 | Oct 20, 2022 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | PTEN: BP4 - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PTEN p.Leu193= variant was identified in 2 of 2194 proband chromosomes (frequency: 0.001) from individuals or families with Cowden syndrome (Nizialek 2015, Sarquis 2006). The variant was also identified in dbSNP (ID: rs568851024) as With other allele, ClinVar (classified as benign by Invitae, GeneDx; as likely benign by Ambry Genetics, Color Genomics; as uncertain significance by Integrated Genetics), Clinvitae, LOVD 3.0, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 27 of 276780 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6458 chromosomes (freq: 0.0003), Latino in 5 of 34416 chromosomes (freq: 0.0002), European in 5 of 126450 chromosomes (freq: 0.00004), Ashkenazi Jewish in 13 of 10142 chromosomes (freq: 0.001), and South Asian in 2 of 30762 chromosomes (freq: 0.0001), while the variant was not observed in the African, East Asian, Finnish, populations. The p.Leu193= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at