chr10-87961118-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000314.8(PTEN):c.1026G>C(p.Lys342Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000314.8 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.1026G>C | p.Lys342Asn | missense_variant, splice_region_variant | Exon 8 of 9 | ENST00000371953.8 | NP_000305.3 | |
PTEN | NM_001304717.5 | c.1545G>C | p.Lys515Asn | missense_variant, splice_region_variant | Exon 9 of 10 | NP_001291646.4 | ||
PTEN | NM_001304718.2 | c.435G>C | p.Lys145Asn | missense_variant, splice_region_variant | Exon 8 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Uncertain:1
This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 342 of the PTEN protein (p.Lys342Asn). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN hamartoma tumor syndrome (PHTS) (PMID: 23335809). ClinVar contains an entry for this variant (Variation ID: 92811). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 10866302, 29785012, 32350270). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.K342N variant (also known as c.1026G>C), located in coding exon 8 of the PTEN gene, results from a G to C substitution at nucleotide position 1026. This change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the lysine to asparagine at codon 342, an amino acid with similar properties. This variant has been reported in individuals with PTEN hamartoma tumor syndrome (PHTS); however, limited clinical details were provided (Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63). In addition, in vitro functional studies showed mixed results on phosphatase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51). The nucleotide and amino acid positions are well conserved and highly conserved, respectively, in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct experimental evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at