10-87863421-CCCCTGCCCTG-CCCCTGCCCTGCCCTG

Variant names:

• chr10-87863421-C-CCCCTG
• rs587781357
• NM_001126049.2:c.-939_-935dupCAGGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001126049.2(KLLN):​c.-939_-935dupCAGGG 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
• Publications: 1 publications found

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]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

MLDHR (HGNC:55481):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 30 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLLN	NM_001126049.2	c.-939_-935dupCAGGG		5_prime_UTR_variant	Exon 1 of 1	ENST00000445946.5	NP_001119521.1
PTEN	NM_000314.8	c.-1049_-1048insCCCTG		upstream_gene_variant		ENST00000371953.8	NP_000305.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLLN	ENST00000445946.5	c.-939_-935dupCAGGG		5_prime_UTR_variant	Exon 1 of 1	6	NM_001126049.2	ENSP00000392204.2
PTEN	ENST00000371953.8	c.-1049_-1048insCCCTG		upstream_gene_variant		1	NM_000314.8	ENSP00000361021.3
MLDHR	ENST00000692337.1	c.-138_-137insCCCTG		upstream_gene_variant				ENSP00000509326.1

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

African (AFR) AF: 0.00114 AC: 7 AN: 6144

American (AMR) AF: 0.000160 AC: 1 AN: 6268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8010

East Asian (EAS) AF: 0.00 AC: 0 AN: 20720

South Asian (SAS) AF: 0.000509 AC: 1 AN: 1966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1150

European-Non Finnish (NFE) AF: 0.0000363 AC: 5 AN: 137704

Other (OTH) AF: 0.0000711 AC: 1 AN: 14072

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

African (AFR) AF: 0.000409 AC: 17 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

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

Aug 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTEN c.-1034_-1030dup variant has been reported in the published literature in a study of patients with PTEN variants who had available brain magnetic resonance imaging (MRI), the patient who was positive for the variant showed no discrete malformation of cortical development (PMID: 32959437 (2020)). The frequency of this variant in the general population, 0.00058 (5/8680 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 11, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 28, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 16, 2013

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16

Splicing

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

Other links and lift over

dbSNP: rs587781357; hg19: chr10-89623178;