NM_001126049.2:c.-840G>A

Variant names:

• chr10-87863327-C-T
• rs563841270
• NM_001126049.2:c.-840G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP2 BS1

This summary comes from the ClinGen Evidence Repository: PTEN c.-1142C>T (NC_000010.10:g.89623084C>T) 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).BS1: Allele frequency of 0.0049 (0.49%, 8/1622 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) BP2: Observed in trans with a pathogenic or likely pathogenic PTEN variant, at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (Internal laboratory contributors SCV000187279.1, SCV000149465.6) LINK:https://erepo.genome.network/evrepo/ui/classification/CA151480/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: KLLN NM_001126049.2 5_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:7
• Conservation: PhyloP100: 0.830
• Publications: 3 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 -5 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126049.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLLN	NM_001126049.2	MANE Select	c.-840G>A		5_prime_UTR	Exon 1 of 1	NP_001119521.1
	MLDHR	NM_001433720.1		c.-232C>T		upstream_gene	N/A	NP_001420649.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLLN	ENST00000445946.5	TSL:6 MANE Select	c.-840G>A		5_prime_UTR	Exon 1 of 1	ENSP00000392204.2
	PTEN	ENST00000688308.1		c.-17+214C>T		intron	N/A	ENSP00000508752.1
	MLDHR	ENST00000692337.1		c.-232C>T		upstream_gene	N/A	ENSP00000509326.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00163 AC: 224 AN: 137082 Hom.: 2 Cov.: 0 AF XY: 0.00152 AC XY: 103 AN XY: 67914

African (AFR) AF: 0.00 AC: 0 AN: 4236

American (AMR) AF: 0.00 AC: 0 AN: 3384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5404

East Asian (EAS) AF: 0.0150 AC: 190 AN: 12636

South Asian (SAS) AF: 0.00 AC: 0 AN: 1170

European-Finnish (FIN) AF: 0.000274 AC: 6 AN: 21924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 696

European-Non Finnish (NFE) AF: 0.000241 AC: 19 AN: 78850

Other (OTH) AF: 0.00102 AC: 9 AN: 8782

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74484

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5162

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000231 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	1	not specified (2)
-	-	2	PTEN hamartoma tumor syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.83
PromoterAI		0.036	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs563841270; hg19: chr10-89623084; COSMIC: COSV64303020; COSMIC: COSV64303020;