chr10-87960876-CTTT-C

Position:

• chr10-87960876-CTTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000314.8(PTEN):​c.802-5_802-3del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,421,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PTEN NM_000314.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.37

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-87960876-CTTT-C is Benign according to our data. Variant chr10-87960876-CTTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229656.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr10-87960876-CTTT-C is described in Lovd as [Likely_benign]. Variant chr10-87960876-CTTT-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.802-5_802-3del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-5_1321-3del		splice_polypyrimidine_tract_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.212-5_212-3del		splice_polypyrimidine_tract_variant, intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-5_802-3del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes AF: 0.0000400 AC: 5 AN: 125120 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000771

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000340

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000188 AC: 244 AN: 1295902 Hom.: 0 AF XY: 0.000180 AC XY: 116 AN XY: 645284

Gnomad4 AFR exome AF: 0.000304

Gnomad4 AMR exome AF: 0.000430

Gnomad4 ASJ exome AF: 0.0000854

Gnomad4 EAS exome AF: 0.0000841

Gnomad4 SAS exome AF: 0.000239

Gnomad4 FIN exome AF: 0.000172

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.0000400 AC: 5 AN: 125120 Hom.: 0 Cov.: 26 AF XY: 0.0000497 AC XY: 3 AN XY: 60398

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000771

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000288

Gnomad4 NFE AF: 0.0000340

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 18, 2023

- -

PTEN hamartoma tumor syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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: rs34003473; hg19: chr10-89720633;