rs762518389
Variant summary
Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.144C>A(p.Asn48Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N48S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 27 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.144C>A | p.Asn48Lys | missense_variant | 2/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.663C>A | p.Asn221Lys | missense_variant | 3/10 | ||
PTEN | NM_001304718.2 | c.-562C>A | 5_prime_UTR_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.144C>A | p.Asn48Lys | missense_variant | 2/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cowden syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 26, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 14675182, 25527629]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 14675182, 17526800, 21659347, 25527629]. - |
PTEN hamartoma tumor syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 48 of the PTEN protein (p.Asn48Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN hamartoma syndrome (PMID: 14675182, 17526800, 24498881, 25527629). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 580731). 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: 14675182, 17942903, 21828076, 24498881, 25527629). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2021 | The p.N48K pathogenic mutation (also known as c.144C>A), located in coding exon 2 of the PTEN gene, results from a C to A substitution at nucleotide position 144. The asparagine at codon 48 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in individuals reported to meet clinical diagnostic criteria for Cowden syndrome (Vega A et al. J. Invest. Dermatol. 2003 Dec;121:1356-9; Morse CB et al. Gynecol. Oncol. Rep. 2015 Apr;12:13-6; Shon W et al. Br J Dermatol, 2014 May;170:1201-4). This alteration was reported as de novo in a 7-year-old child with clinical features of PTEN hamartoma tumor syndrome (Lachlan KL et al. J. Med. Genet. 2007 Sep;44:579-85). This alteration was also reported in several individuals suspected of having Cowden syndrome (Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Nieuwenhuis MH et al. Fam. Cancer 2014 Mar;13:57-63; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). In a functional study using a yeast-based assay, this variant demonstrated severely reduced phosphatase activity when compared to wild type PTEN and was similar to the catalytic dead control (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42). In several studies, this variant showed normal protein expression that was comparable to wild type PTEN, but demonstrated reduced PTEN function (Vega A et al. J. Invest. Dermatol. 2003; Andrés-Pons A et al. Cancer Res. 2007 Oct;67:9731-9 Dec;121:1356-9; Spinelli L et al. J. Med. Genet. 2015 Feb;52:128-34). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am. J. Hum. Genet. 2018 05;102:943-955). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 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)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Glioma susceptibility 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 13, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at