rs1554826052

chr10-87965387-A-AAT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000314.8(PTEN):c.1127_1128insAT(p.His376GlnfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.18

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87965387-A-AAT is Pathogenic according to our data. Variant chr10-87965387-A-AAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486976.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.1127_1128insAT	p.His376GlnfsTer41	frameshift_variant	9/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1646_1647insAT	p.His549GlnfsTer41	frameshift_variant	10/10
PTEN	NM_001304718.2	c.536_537insAT	p.His179GlnfsTer41	frameshift_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.1127_1128insAT	p.His376GlnfsTer41	frameshift_variant	9/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2017

The c.1127_1128insAT variant, located in coding exon 9 of the PTEN gene, results from an insertion of two nucleotides at position 1127, causing a translational frameshift with a predicted alternate stop codon (p.H376Qfs*41). This frameshift occurs at the 3' terminus of PTEN, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 12 amino acids. Internal structural analysis of this region concluded that the burden of experimental literature points to this region being crucial for regulation of PTEN activity (Georgescu MM et al. Proc. Natl. Acad. Sci. U.S.A., 1999 Aug;96:10182-7; Hopkins BD et al. Trends Biochem. Sci., 2014 Apr;39:183-90; Sun Z et al. Cell Rep, 2014 Mar;6:844-54; Vazquez F et al. Mol. Cell. Biol., 2000 Jul;20:5010-8). Additionally, other alterations also resulting in an elongated PTEN protein have been observed in individuals with PTEN-related disorders. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554826052; hg19: chr10-89725144;