rs1131690935

Variant names:

• chr19-1221972-AAGAGGTTCTCCATCCGGC-A
• rs1131690935
• NM_000455.5:c.890_907delGGTTCTCCATCCGGCAGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP5_Moderate

The NM_000455.5(STK11):​c.890_907delGGTTCTCCATCCGGCAGA​(p.Arg297_Gln302del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R297R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.73
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial pancreatic carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Peutz-Jeghers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 34 uncertain in NM_000455.5
• 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 VariationId is 428771.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.890_907delGGTTCTCCATCCGGCAGA	p.Arg297_Gln302del	disruptive_inframe_deletion	Exon 7 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.890_907delGGTTCTCCATCCGGCAGA	p.Arg297_Gln302del	disruptive_inframe_deletion	Exon 7 of 9		NP_001394184.1
STK11	NR_176325.1	n.2157_2174delGGTTCTCCATCCGGCAGA		non_coding_transcript_exon_variant	Exon 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.890_907delGGTTCTCCATCCGGCAGA	p.Arg297_Gln302del	disruptive_inframe_deletion	Exon 7 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.890_907delGGTTCTCCATCCGGCAGA	p.Arg297_Gln302del	disruptive_inframe_deletion	Exon 7 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.518_535delGGTTCTCCATCCGGCAGA	p.Arg173_Gln178del	disruptive_inframe_deletion	Exon 9 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*715_*732delGGTTCTCCATCCGGCAGA		non_coding_transcript_exon_variant	Exon 8 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*715_*732delGGTTCTCCATCCGGCAGA		3_prime_UTR_variant	Exon 8 of 11	3		ENSP00000466610.1

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

Feb 19, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1131690935; hg19: chr19-1221971;