rs786204940
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7
The ENST00000692337.1(ENSG00000289051):c.75C>T(p.Ser25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 391,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 0 hom. )
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.782
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.28).
BP6
?
Variant 10-87863633-C-T is Benign according to our data. Variant chr10-87863633-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 189497.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
?
Synonymous conserved (PhyloP=0.782 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.-837C>T | 5_prime_UTR_variant | 1/9 | ENST00000371953.8 | ||
PTEN | NM_001304717.5 | c.-317C>T | 5_prime_UTR_variant | 1/10 | |||
PTEN | NM_001304718.2 | c.-1541C>T | 5_prime_UTR_variant | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENST00000692337.1 | c.75C>T | p.Ser25= | synonymous_variant | 1/1 | P1 | ||||
PTEN | ENST00000371953.8 | c.-837C>T | 5_prime_UTR_variant | 1/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152080Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000501 AC: 12AN: 239332Hom.: 0 Cov.: 0 AF XY: 0.0000493 AC XY: 6AN XY: 121594
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74296
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:2Benign:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 08, 2021 | Variant summary: PTEN c.-837C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 4.6e-05 in 150856 control chromosomes (gnomAD v3.1.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-837C>T has been reported in the literature in a Cowden syndrome study (Nizialek_2015). This report does not provide unequivocal conclusions about association of the variant with Cowden Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters including an expert panel (ClinGen PTEN Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2023 | Describes a nucleotide substitution 837 basepairs upstream of the ATG translational start site in the PTEN promoter region; Observed in individuals with features of Cowden syndrome (PMID: 25669429); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.-836C>T; This variant is associated with the following publications: (PMID: 25669429) - |
PTEN hamartoma tumor syndrome Benign:1
Likely benign, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Oct 11, 2023 | NM_000314.8(PTEN):c.-837C>T 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). BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00003249 [0.003249%] in gnomAD v3. BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributor(s)) - |
Computational scores
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BayesDel_noAF
Benign
CADD
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DANN
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at