rs786204933
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000314.8(PTEN):c.437T>A(p.Leu146*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000314.8 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.437T>A | p.Leu146* | stop_gained | Exon 5 of 9 | ENST00000371953.8 | NP_000305.3 | |
PTEN | NM_001304717.5 | c.956T>A | p.Leu319* | stop_gained | Exon 6 of 10 | NP_001291646.4 | ||
PTEN | NM_001304718.2 | c.-314T>A | 5_prime_UTR_variant | Exon 4 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This mutation is denoted PTEN c.437T>A at the cDNA level and p.Leu14Ter (L146X) at the protein level. The substitution creates a nonsense variant, changing a Leucine to a premature stop codon (TTA>TAA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not been published as a germline pathogenic variant to our knowledge, it has been reported as a somatic mutation in association with endometrial cancer (Catasus 2008, Murayama-Hosokawa 2001). Exon 5 of the PTEN gene has been described as a mutational hot-spot, and, in one study, almost half of all Cowden syndrome-associated PTEN mutations were identified in this exon (Marsh 1998). Based on current information, we consider this variant to be pathogenic. The PTEN hamartoma tumor syndrome (PHTS) conditions associated with cancer risk include Cowden Syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRRS). The cancer risks include approximately 25-45% risk for breast cancer in women, 5-10% risk for endometrial cancer in women, and 10% risk for non-medullary thyroid cancer in men and women (Hobert 2009). In addition to the cancer risks, these autosomal dominant conditions include other distinct features. Individuals with CS typically have one or more features including an increased head circumference in at least the 97th percentile (macrocephaly), trichilemmomas, papillomatous papules, and the pathognomonic finding of cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease). BRRS is associated with macrocephaly, intestinal hamartomas, pigmented macules of the glans penis, and can be associated with developmental delay or autism. CS is also associated with benign conditions including benign breast disease, thyroid goiters, benign gastrointestinal polyps, and uterine fibroids. Vascular abnormalities, such as hemangiomas and arteriovenous malformations have also been reported individuals with PTEN mutations. Of note, a recent prospective study of individuals with germline PTEN mutations has suggested that the cancer risks may be higher than previously reported as well as expanding the cancer spectrum to include increased risks for colorectal cancer, kidney cancer, and melanoma (Tan 2012). Male breast cancer has also been reported in patients with a PTEN mutation (Fackenthal 2001). -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.L146* pathogenic mutation (also known as c.437T>A), located in coding exon 5 of the PTEN gene, results from a T to A substitution at nucleotide position 437. This changes the amino acid from a leucine to a stop codon within coding exon 5. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at