rs786204859
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP2PS4_SupportingPS3PS2PM2
This summary comes from the ClinGen Evidence Repository: PTEN c.407G>A (p.C136Y) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). 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) SCV000222113.9)PS3: Phosphatase activity <50% of wild-type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 10866302)PM2: 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.PS4_P: Probands with specificity score of 1-1.5. (PMID 9735393, internal laboratory contributor(s) SCV000222113.9) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000451/MONDO:0017623/003
Frequency
Consequence
NM_001304718.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.407G>A | p.Cys136Tyr | missense_variant | Exon 5 of 9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304718.2 | c.-344G>A | 5_prime_UTR_premature_start_codon_gain_variant | Exon 4 of 9 | NP_001291647.1 | |||
| PTEN | NM_001304717.5 | c.926G>A | p.Cys309Tyr | missense_variant | Exon 6 of 10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.-344G>A | 5_prime_UTR_variant | Exon 4 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:2
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 136 of the PTEN protein (p.Cys136Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (CD) and Bannayan-Riley-Ruvalcaba syndrome (PMID: 9735393, 20600018, 21194675, 21659347). ClinVar contains an entry for this variant (Variation ID: 189406). 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 9735393, 10866302). This variant disrupts the p.Cys136 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10848731, 20600018, 21659347, 23886400, 24778394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
PTEN c.407G>A (p.C136Y) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). 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) SCV000222113.9) PS3: Phosphatase activity <50% of wild-type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 10866302) PM2: 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. PS4_P: Probands with specificity score of 1-1.5. (PMID 9735393, internal laboratory contributor(s) SCV000222113.9) -
Cowden syndrome 1 Pathogenic:1
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9735393, 16773562]. -
Malignant tumor of urinary bladder Pathogenic:1
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect: loss of phosphatase activity (Han 2000, Mighell 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11668501, 16773562, 32378608, 21956414, 12938083, 17941496, 15492994, 21659347, 10866302, 21194675, 29706350, 9735393, 20600018, 19457929, 24475377, 30561760, 30736836, 30787465) -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C136Y pathogenic mutation (also known as c.407G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 407. The cysteine at codon 136 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported in individuals meeting clinical criteria for PTEN Hamartoma Tumor Syndrome (PHTS)/Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Sarquis MS et al. Am. J. Hum. Genet., 2006 Jul;79:23-30; Heald B et al. Gastroenterology, 2010 Dec;139:1927-3; Ngeow J et al. J Clin Endocrinol Metab. 2011 Dec;96(12):E2063-71; Tan MH et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one family in our clinical cohort (Ambry internal data). In two separate functional studies, lipid phosphatase activity for this variant was functionally deficient (Han SY et al. Cancer Res., 2000 Jun;60:3147-51; Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). Two other alterations at the same codon, p.C136R (c.406T>C) and p.C136F (c.407G>T), have been detected in individuals with features consistent with PTEN Hamartoma Tumor Syndrome (PHTS) (Kubo Y et al. Br. J. Dermatol. 2000 Jun;142(6):1100-5; Jenny B et al. J. Neurosurg. 2007 Oct;107(4 Suppl):307-13; Venturini G et al. Ophthalmology 2012 Apr;119(4):857-64; Galatola M et al. BMC Med. Genet., 2012 Apr;13:28; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; He X et al. Cancer Res. 2013 May;73(10):3029-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at