rs1131690935

Positions:

• chr19-1221972-AAGAGGTTCTCCATCCGGC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The NM_000455.5(STK11):​c.890_907del​(p.Arg297_Gln302del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.73

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain 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.
• PP5: Variant 19-1221972-AAGAGGTTCTCCATCCGGC-A is Pathogenic according to our data. Variant chr19-1221972-AAGAGGTTCTCCATCCGGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428771.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.890_907del	p.Arg297_Gln302del	inframe_deletion	7/10	ENST00000326873.12
STK11	NM_001407255.1	c.890_907del	p.Arg297_Gln302del	inframe_deletion	7/9
STK11	NR_176325.1	n.2157_2174del		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.890_907del	p.Arg297_Gln302del	inframe_deletion	7/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2016

The c.890_907del18 variant (also known as p.R297_Q302del) is located in coding exon 7 of the STK11 gene. This variant results from an in-frame deletion of 18 nucleotides (GGTTCTCCATCCGGCAGA) between nucleotide positions 890 and 907. This results in the deletion of 6 amino acid residues between codons 297 and 302. This alteration has been identified in an individual with a clinical diagnosis of Peutz-Jeghers syndrome (Ambry internal data). Other alterations occurring in this region have been shown to be pathogenic (Wang Z, Hum. Mutat. 2014 Jul; 35(7):851-8; Westerman AM, Hum. Mutat. 1999 ; 13(6):476-81), however this specific variant has not been reported in the literature to date. 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 6026 samples (12052 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. The deleted amino acid positions are well conserved in available vertebrate species. In addition, this deletion is predicted to be highly deleterious by the PROVEAN in silico analysis tool (Choi Y, PLoS ONE 2012 ; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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: rs1131690935; hg19: chr19-1221971;