rs1131690916

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_162del(p.Met51_Leu54del) variant causes a 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). Synonymous variant affecting the same amino acid position (i.e. Y49Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with SIRT1 (size 45) in uniprot entity STK11_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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	UniProt
STK11	NM_000455.5	c.151_162del	p.Met51_Leu54del	inframe_deletion	1/10	ENST00000326873.12
STK11	NM_001407255.1	c.151_162del	p.Met51_Leu54del	inframe_deletion	1/9
STK11	NR_176325.1	n.1287_1298del		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.151_162del	p.Met51_Leu54del	inframe_deletion	1/10	1	NM_000455.5	P1

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

Feb 12, 2015

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 alteration has been identified in individuals with a clinical diagnosis of Peutz-Jeghers syndrome (Resta N, Dig Liver Dis 2013 Jul; 45(7):606-11, Ambry interal 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 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. In the ESP, this variant was not observed in 6255 samples (12510 alleles) with coverage at this position.To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 75,000 alleles tested) in our clinical cohort. Based on protein sequence alignment, these amino acids are highly conserved in available vertebrate species. 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

Invitae

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;