10-87863421-CCCCTGCCCTG-CCCCTGCCCTGCCCTG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001126049.2(KLLN):c.-935_-934insCAGGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 370,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: KLLN NM_001126049.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.159

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 -4 ACMG points.

• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLLN	NM_001126049.2	c.-935_-934insCAGGG		5_prime_UTR_variant	1/1	ENST00000445946.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLLN	ENST00000445946.5	c.-935_-934insCAGGG		5_prime_UTR_variant	1/1		NM_001126049.2	P1
PTEN	ENST00000688308.1	c.-17+323_-17+327dup		intron_variant				P1
PTEN	ENST00000693560.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000687 AC: 15 AN: 218352 Hom.: 0 Cov.: 0 AF XY: 0.0000721 AC XY: 8 AN XY: 110980

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000509

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000363

Gnomad4 OTH exome AF: 0.0000711

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74486

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2019	Has not been previously published as pathogenic or benign to our knowledge; Variants within the PTEN promoter have been observed in individuals with features of Cowden syndrome (Zhou 2003); Also known as c.-1033_-1029dupGCCCT; This variant is associated with the following publications: (PMID: 12844284, 22679820) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 28, 2023

Variant summary: PTEN c.-1034_-1030dupGCCCT is located in the untranslated mRNA region upstream of the initiation codon, and involves the insertion of five nucleotides in the PTEN promoter region; variants in this region might alter transcription, which could result in impaired mRNA expression. PTEN is unique in that its promoter and its 5 UTR overlap, so variants in this region might also affect mRNA splicing and protein translation. The variant allele was found at a frequency of 0.00012 in 370652 control chromosomes (gnomAD v4.0.0). The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06),, suggesting that the variant may be benign. To our knowledge, no occurrence of c.-1034_-1030dupGCCCT in individuals affected with PTEN-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. The following publication was ascertained in the context of this evaluation (PMID: 32959437). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2013

- -

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: rs587781357; hg19: chr10-89623178;