rs1131690916

Positions:

• chr19-1207058-TACCTGATGGGGG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000455.5(STK11):​c.151_162delATGGGGGACCTG​(p.Met51_Leu54del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.65

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]

STK11 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000455.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-1207058-TACCTGATGGGGG-T is Pathogenic according to our data. Variant chr19-1207058-TACCTGATGGGGG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428748.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr19-1207058-TACCTGATGGGGG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.151_162delATGGGGGACCTG	p.Met51_Leu54del	conservative_inframe_deletion	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.151_162delATGGGGGACCTG	p.Met51_Leu54del	conservative_inframe_deletion	1/9		NP_001394184.1
STK11	NR_176325.1	n.1287_1298delATGGGGGACCTG		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.151_162delATGGGGGACCTG	p.Met51_Leu54del	conservative_inframe_deletion	1/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.151_162delATGGGGGACCTG	p.Met51_Leu54del	conservative_inframe_deletion	1/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11353_-82-11342delATGGGGGACCTG		intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.151_162delATGGGGGACCTG		non_coding_transcript_exon_variant	1/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.151_162del12 variant (also known as p.M51_L54del) is located in coding exon 1 of the STK11 gene. This variant results from an in-frame deletion of 12 nucleotides at positions 151 to 162. This results in the deletion of four amino acids at codons 51 to 54. This variant has been observed in individuals with a personal and/or family history that is consistent with Peutz-Jeghers syndrome (Resta N, Dig Liver Dis 2013 Jul; 45(7):606-11; Ambry internal data). Additionally, structural analysis has concluded that this alteration deleteriously affects an adjacent and essential ATP binding loop, and thus, leads to a deleterious functional effect on the protein (Zeqiraj E, Science 2009 Dec;326(5960):1707-11). This amino acid region is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Peutz-Jeghers syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 10, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 428748). This variant has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 23415580). This variant is not present in population databases (gnomAD no frequency). This variant, c.151_162del, results in the deletion of 4 amino acid(s) of the STK11 protein (p.Met51_Leu54del), but otherwise preserves the integrity of the reading frame. -

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: rs1131690916; hg19: chr19-1207057;