rs864622341
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PP2PS2PM2_SupportingPS4_Supporting
This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.521A>G (p.Tyr174Cys) variant meets criteria to be classified as likely pathogenic 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000602123.1)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s) SCV000602123.1).PM2_P: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score=0.978). LINK:https://erepo.genome.network/evrepo/ui/classification/CA349032/MONDO:0017623/003
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.521A>G | p.Tyr174Cys | missense_variant | 6/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.1040A>G | p.Tyr347Cys | missense_variant | 7/10 | ||
PTEN | NM_001304718.2 | c.-71A>G | 5_prime_UTR_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.521A>G | p.Tyr174Cys | missense_variant | 6/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461194Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726922
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Jun 14, 2023 | NM_000314.8(PTEN):c.521A>G (p.Tyr174Cys) variant meets criteria to be classified as likely pathogenic 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000602123.1) PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s) SCV000602123.1). PM2_P: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score=0.978). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 174 of the PTEN protein (p.Tyr174Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 31594918; external communication). In at least one individual the variant was observed to be de novo. This variant is also known as c.464T>G (p.Tyr155Cys). ClinVar contains an entry for this variant (Variation ID: 220007). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 06, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2018 | This variant is denoted PTEN c.521A>G at the cDNA level, p.Tyr174Cys (Y174C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a metastatic melanoma lesion (Wang 2010). Additionally, a different missense variant at the same residue, PTEN Tyr174Asn, demonstrated loss of phosphatase activity in an in vitro assay (Han 2000). PTEN Tyr174Cys was not observed in large population cohorts (Lek 2016). This variant is located in the Phosphatase domain (Molinari 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence and internal data, we consider PTEN Tyr174Cys to be likely pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2022 | The p.Y174C pathogenic mutation (also known as c.521A>G), located in coding exon 6 of the PTEN gene, results from an A to G substitution at nucleotide position 521. The tyrosine at codon 174 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been confirmed as a de novo variant in a child meeting clinical criteria for PTEN hamartoma tumor syndrome (PHTS) and has been reported in PHTS cohort studies (Mester JL et al. Hum Mutat, 2018 11;39:1581-1592; Busch RM et al. Transl Psychiatry, 2019 10;9:253; Shao DD et al. Ann Neurol, 2020 12;88:1153-1164). Based on internal analysis, p.Y174C is structurally deleterious (Lee JO et al. Cell, 1999 Oct;99:323-34; Han SY et al. Cancer Res, 2000 Jun;60:3147-51). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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. - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at