NM_000314.8:c.737C>T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2PS4PM2PS2
This summary comes from the ClinGen Evidence Repository: PTEN c.737C>T (p.P246L) 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_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 23934111, internal laboratory contributor(s) SCV000222227.10)PS4: Probands with phenotype specificity score of 4-15.5. (PMID 24375884, PMID 10076877, PMID 22261759, PMID 23934111, internal laboratory contributor(s) SCV000222227.10)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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000559/MONDO:0017623/003
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.737C>T | p.Pro246Leu | missense_variant | Exon 7 of 9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304717.5 | c.1256C>T | p.Pro419Leu | missense_variant | Exon 8 of 10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.146C>T | p.Pro49Leu | missense_variant | Exon 7 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461802Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727208
GnomAD4 genome
ClinVar
Submissions by phenotype
Cowden syndrome 1 Pathogenic:5
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This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012, 32350270]. -
This c.737C>T (p.Pro246Leu) variant was detected in 3 members of a family with Bannayan-Riley-Ruvalcaba syndrome (BRRS) [PMID 10400993]. BRRS is allelic to Cowden syndrome and is characterized by macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis. The variant was further detected de novo in a cohort of 264 trio diagnosed with seizure. The patient had infantile spasms in addition to vascular anomalies and macrocephaly [PMID 23934111]. We have observed this variant, de novo, in a patient with autism in our internal database. This c.737C>T (p.Pro246Leu) variant was not observed in the gnomAD population database. Proline at amino acid position 246 is conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Pro246Leu to be deleterious. This variant is thus classified as pathogenic. -
not provided Pathogenic:5
The PTEN c.737C>T (p.Pro246Leu) variant has been reported in the published literature in individuals meeting Cownden syndrome diagnostic criteria (PMIDs: 27477328 (2017), 24375884 (2014), 22261759 (2012)). This variant has been identified as a de novo occurrence in an individual with epileptic encephalopathies (PMID: 23934111 (2013)). Functional evidence suggests that this variant may impact protein function (PMIDs: 23934111 (2013), 21828076 (2011), 14566704 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
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Observed in multiple unrelated patients with features of PTEN Hamartoma Tumor syndrome referred for genetic testing at GeneDx and in published literature (Marsh 1999, Zhou 2003, Hobert 2012, Vanderver 2014); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect: partial loss of phosphastase activity and protein instability (Andres-Pons 2007, Rodriguez-Escudero 2011, Mighell 2018, Matreyek 2018); 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: 27477328, 10923032, 26681312, 10076877, 17942903, 25669429, 23934111, 12938083, 21194675, 14566704, 25527629, 23161105, 14518068, 24744697, 22261759, 24375884, 10400993, 15805158, 27146902, 30555518, 28152038, 28263302, 30174244, 31336731, 31046523, 21828076, 29706350, 31447099, 32162695, 33726816, 18626510) -
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PTEN hamartoma tumor syndrome Pathogenic:4
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 246 of the PTEN protein (p.Pro246Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with symptoms consistent with PTEN hamartoma tumor syndrome (PHTS) (PMID: 10076877, 22261759, 23934111, 24375884, 27477328). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as chr10:89717712 C>T. ClinVar contains an entry for this variant (Variation ID: 142269). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTEN protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 14566704, 17942903, 21828076). For these reasons, this variant has been classified as Pathogenic. -
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (PTEN C2 domain; NCBI). (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple patients with PTEN hamartoma tumor syndrome and Cowden syndrome (ClinVar, PMID: 27477328). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies in yeast cells demonstrated partially impaired phosphatase activity (PMID: 21828076). (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
The p.Pro246Leu variant in PTEN has been reported in at least 3 individuals with PTEN-associated phenotypes: 1 with Bannayan-Riley-Ruvalcaba syndrome (BRRS), 1 with Lhermitte-Duclos disease (LDD), and 1 with colon cancer and segregated with BRRS in 2 affected relatives (Marsh 1999, Otto 1999, Zhou 2003, Hobert 2012, Su sswein 2016). In addition, it was reported as a de novo occurrence in an infant with infantile spasms and clinical features of a PTEN hamartoma tumor syndrome ( Allen 2013). Functional studies provide some evidence that the p.Pro246Leu varia nt is associated with decreased protein activity (Rodriguez-Escudero 2011). This variant was absent from large population studies. In summary, although addition al studies are required to fully establish its clinical significance, the p.Pro2 46Leu variant is likely pathogenic. -
PTEN c.737C>T (p.P246L) 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_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 23934111, internal laboratory contributor(s) SCV000222227.10) PS4: Probands with phenotype specificity score of 4-15.5. (PMID 24375884, PMID 10076877, PMID 22261759, PMID 23934111, internal laboratory contributor(s) SCV000222227.10) 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. -
Breast and/or ovarian cancer Pathogenic:1
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Gastric cancer Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.737C>T (p.P246L) alteration is located in exon 7 (coding exon 7) of the PTEN gene. This alteration results from a C to T substitution at nucleotide position 737, causing the proline (P) at amino acid position 246 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported as heterozygous in multiple individuals who met clinical criteria for PTEN hamartoma tumor syndrome, and was determined to be the result of a de novo mutation in one individual (Hobert, 2012; Vanderver, 2014; Shao, 2020). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). A yeast-based assay demonstrated that this alteration combined with another missense alteration failed to rescue yeast cells from p110alpha CAAX induced growth inhibition and release GFP-AKt1 from the cellular membrane, although both alterations by themselves had similar activity to wildtype. The authors postulated that this assay suggests patient-dependent loss of function effects (Andrés-Pons, 2007). In addition, p.P246L has been described as a pathogenic mutation leading to impaired PTEN protein levels and signaling in Lhermitte-Dulcose disease cells (Zhou, 2003). In another functional assay, this variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at