rs1554898088

Variant names:

• chr10-87933065-ACC-A
• rs1554898088
• NM_000314.8:c.308_309delCC

Your query was ambiguous. Multiple possible variants found:

• chr10-87933065-ACC-A
• chr10-87933065-ACC-AC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000314.8(PTEN):​c.308_309delCC​(p.Pro103LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.51

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87933065-ACC-A is Pathogenic according to our data. Variant chr10-87933065-ACC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 450893.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.308_309delCC	p.Pro103LeufsTer3	frameshift_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.827_828delCC	p.Pro276LeufsTer3	frameshift_variant	Exon 6 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-443_-442delCC		5_prime_UTR_variant	Exon 4 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.308_309delCC	p.Pro103LeufsTer3	frameshift_variant	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 27, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.308_309delCC variant in the PTEN gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This deletion causes a frameshift starting with codon Proline 103, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Pro103LeufsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, the c.308_309delCC variant is a strong candidate for a pathogenic variant. However, the possibility it could be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554898088; hg19: chr10-89692822;