19-1221940-TCTC-T

Position:

• chr19-1221940-TCTC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The ENST00000326873.12(STK11):​c.863-5_863-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000045 in 1,554,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: STK11 ENST00000326873.12 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.247

Genes affected

STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 19-1221940-TCTC-T is Benign according to our data. Variant chr19-1221940-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420387.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.863-5_863-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.863-5_863-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001394184.1
STK11	NR_176325.1	n.2130-5_2130-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.863-5_863-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1401864 Hom.: 0 AF XY: 0.00000434 AC XY: 3 AN XY: 691946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000370

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 14, 2021	This variant causes a deletion of 3 nucleotides from the -3 to -5 positions in intron 6 of the STK11 gene. Splice site prediction tools suggest that this variant may have an impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 03, 2022

Variant summary: STK11 c.863-5_863-3delCTC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Four computational tools predict the variant weakens a 3 acceptor site. c.863-5_863-3delCTC has been reported in the literature in an individual that did not have any clinical characteristics of Peutz-Jeghers syndrome. RNAseq analysis of the patient blood sample revealed an abnormal transcript that lacks exon 7. However, this out-of-frame transcript was minorly expressed (only in 0.9%), implying that the variant causes an insignificant splicing abnormality (Dragos_2021). The variant was absent in 159362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Co-occurrence with a pathogenic variant has been observed via internal testing (BRCA2 c.100G>T, p.E34X). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and as likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing.; Observed in a patient without clinical features of Peutz-Jeghers syndrome, and demonstrated to have a very minor impact on splicing (PMID: 34439939); This variant is associated with the following publications: (PMID: 34439939) -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Jul 14, 2021

STK11:c.863-5_863-3del variant was detected in 1 patient without Peutz-Jeghers phenotype. The variants is predicted to abolish natural acceptor splice site in intron 6 by in silico splicing tools. Functional RNA study has shown that the variant causes insignificant splicing aberration (PMID: 34439939). Therefore the variant was classified as likely benign (ACMG/AMP: BS3, BP5, PM2). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs764739106; hg19: chr19-1221939;