rs587781340

Positions:

• chr10-87863269-TGCAAAAGCCGCA-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP5 BS4_Supporting

This summary comes from the ClinGen Evidence Repository: PTEN c.-1195del12 (NC_000010.10:g.89623031_89623042delAAGCCGCAGCAA) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS4_P: Lack of segregation in affected members of one family. (Internal laboratory contributor SCV SCV000222146.7)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributors SCV000222146.7, SCV000183826.5) LINK:https://erepo.genome.network/evrepo/ui/classification/CA163819/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: KLLN NM_001126049.2 5_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 2.18

Genes affected

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

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_benign. Variant got -2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLLN	NM_001126049.2	c.-794_-783del		5_prime_UTR_variant	1/1	ENST00000445946.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLLN	ENST00000445946.5	c.-794_-783del		5_prime_UTR_variant	1/1		NM_001126049.2	P1
PTEN	ENST00000688308.1	c.-17+161_-17+172del		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000221 AC: 18 AN: 81476 Hom.: 0 AF XY: 0.000203 AC XY: 8 AN XY: 39340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000580

Gnomad4 ASJ exome AF: 0.000298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000379

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000332

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	This variant is associated with the following publications: (PMID: 21194675, 21956414, 25669429, 28821472, 28157521, 21532617) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 16, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	KLLN: BS1, BS2; PTEN: BS1, BS2 -

PTEN hamartoma tumor syndrome Uncertain:1 Benign:1

Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Mar 05, 2019	PTEN c.-1195del12 (NC_000010.10:g.89623031_89623042delAAGCCGCAGCAA) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). BS4_P: Lack of segregation in affected members of one family. (Internal laboratory contributor SCV SCV000222146.7) BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributors SCV000222146.7, SCV000183826.5) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 21, 2020	This variant occurs in a non-coding region of the PTEN gene. It does not change the encoded amino acid sequence of the PTEN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 21194675, 21532617). This variant is also known as c.-1195del12 in the literature. ClinVar contains an entry for this variant (Variation ID: 189433). This variant has been reported to have conflicting or insufficient data to determine the effect on PTEN protein function (PMID: 21532617). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 24, 2019	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

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

Publications

LitVar

Other links and lift over

dbSNP: rs587781340; hg19: chr10-89623026;