rs121909227
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000314.8(PTEN):c.640C>T(p.Gln214Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q214Q) has been classified as Likely benign. 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.640C>T | p.Gln214Ter | stop_gained | 7/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.1159C>T | p.Gln387Ter | stop_gained | 8/10 | ||
PTEN | NM_001304718.2 | c.49C>T | p.Gln17Ter | stop_gained | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.640C>T | p.Gln214Ter | stop_gained | 7/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461642Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727126
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cowden syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 29, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
PTEN hamartoma tumor syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 18, 2023 | This sequence change creates a premature translational stop signal (p.Gln214*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 7827). This premature translational stop signal has been observed in individual(s) with a diagnosis or suspicion of Cowden syndrome (PMID: 9832032, 10606430, 17954274, 21659347, 23160955, 27477328, 28086757). In at least one individual the variant was observed to be de novo. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2017 | This pathogenic variant is denoted PTEN c.640C>T at the cDNA level and p.Gln214Ter (Q214X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PTEN Gln214Ter has been reported in several patients with Cowden syndrome (Longy 1998, Sanson 1999, Bussaglia 2002, Tan 2011, Chen 2016), as well as in an individual with breast and other cancers but without typical features of Cowden syndrome (Tate 2007). We consider this variant to be pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2019 | The p.Q214* pathogenic mutation (also known as c.640C>T), located in coding exon 7 of the PTEN gene, results from a C to T substitution at nucleotide position 640. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration was confirmed as a de novo mutation in a patient meeting clinical criteria for Bannayan-Riley-Ruvalcaba (BRR) syndrome (Longy M et al. J. Med. Genet. 1998 Nov;35:886-9). This mutation has also been seen in multiple patients with Cowden syndrome (Bussaglia E et al. J. Invest. Dermatol. 2002 Apr;118:639-44; Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Kato K et al. Brain Dev. 2018 Sep;40(8):678-684) and in individuals with autism (O'Roak BJ et al. Science 2012 Dec;338:1619-22; Kosmicki J et al. Nat. Genet. 2017 Apr;49(4):504-510). Tate et al. report this mutation in an individual with hepatic angiosarcoma, breast and pharyngeal cancer, thyroid clear cell adenoma, and uterine leiomyoma (Tate G et al. Cancer Genet. Cytogenet. 2007 Oct;178:160-2). In addition to the clinical data presented in the literature, 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. - |
Macrocephaly-autism syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences | Nov 01, 2015 | Patient, a 4 year-old girl, showed mild developmental delay and dysmorphic facial features. Her last head circumference was 57 cm (+4.1SD). The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at