rs886039554

Positions:

• chr19-1220506-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.597+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.86

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 Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-1220506-G-T is Pathogenic according to our data. Variant chr19-1220506-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1220506-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.597+1G>T		splice_donor_variant		ENST00000326873.12
STK11	NM_001407255.1	c.597+1G>T		splice_donor_variant
STK11	NR_176325.1	n.1864+1G>T		splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.597+1G>T		splice_donor_variant		1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 10, 2018	This variant is not present in population databases (ExAC no frequency). This variant has been reported in at least one individual affected with Peutz-Jeghers syndrome (PMID: 16407375). The variant is also known as IVS4+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 265451). A different variant affecting this nucleotide (c.597+1G>A) has been determined to be pathogenic (PMID: 21118512). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 4 of the STK11 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2016

The c.597+1 G>T splice site variant in the STK11 gene has been previously reported in association with Peutz-Jeghers syndrome (Mehenni et al., 2006). This variant destroys the canonical splice donor site in intron 4, and is expected to cause abnormal gene splicing. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2013

​The c.597+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 4 of the STK11 gene. This alteration has been described in a patient with Peutz-Jeghers syndrome with colon cancer (Mehenni H et al. Gut 2006; 55:984-90). Two other alterations at this nucleotide (c.597+1G>A and c.597+1G>C) have also been described in patients with Peutz-Jeghers syndrome (Papp J et al. BMC Med. Genet. 2010; 11:169, Hearle N et al. Clin. Cancer Res. 2006; 12:3209-15). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 20,000 alleles tested) in our clinical cohort (includes this individual). This nucleotide position is completely conserved on sequence alignment.Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish or significantly weaken the native splice donor site, respectively. However, direct evidence is unavailable.Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.597+1G>T variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -2
DS_DL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039554; hg19: chr19-1220505; COSMIC: COSV58827522; COSMIC: COSV58827522;