chr10-87864555-A-G
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_000314.8(PTEN):c.79+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
NM_000314.8 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.79+7A>G | splice_region_variant, intron_variant | ENST00000371953.8 | |||
PTEN | NM_001304717.5 | c.598+7A>G | splice_region_variant, intron_variant | ||||
PTEN | NM_001304718.2 | c.-626+7A>G | splice_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.79+7A>G | splice_region_variant, intron_variant | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461190Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17AN XY: 726966
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2019 | Variant summary: PTEN c.79+7A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. One publication reports that sequencing of cDNA from patient lymphoblast cell lines with the variant resulted in no detecatble aberrations in splicing (Chen_2017). The variant allele was found at a frequency of 1.2e-05 in 251482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.79+7A>G has been reported in the literature in individuals affected with Cowden Syndrome without strong evidence for causality (e.g. Pilarski_2011, Chen_2017). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. Five laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) with conflicting interpretations: two laboratories cited the variant as likely benign, two cited the variant as uncertain significance, and one cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2017 | 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. - |
PTEN hamartoma tumor syndrome Benign:2
Likely benign, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Jun 14, 2023 | NM_000314.8(PTEN):c.79+7A>G variant meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID: 28677221) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Cowden syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute | May 26, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2023 | This variant causes an A to G nucleotide substitution at the +7 position of intron 1 of the PTEN gene. A functional study reports no RNA defect using patient-derived cells, although no data was shown (PMID: 28677221). This variant has been reported in individuals affected with Cowden or Cowden-like syndrome (PMID: 25669429, 28677221). This variant has been identified in 3/251482 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
PTEN-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 07, 2019 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at