rs397518440

Positions:

• chr19-1219366-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000326873.12(STK11):​c.418del​(p.Leu140TrpfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L140L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 ENST00000326873.12 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.98

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1219366-GC-G is Pathogenic according to our data. Variant chr19-1219366-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 7449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.418del	p.Leu140TrpfsTer21	frameshift_variant	3/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.418del	p.Leu140TrpfsTer21	frameshift_variant	3/9		NP_001394184.1
STK11	NR_176325.1	n.1685del		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.418del	p.Leu140TrpfsTer21	frameshift_variant	3/10	1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 19, 2022	This sequence change creates a premature translational stop signal (p.Leu140Trpfs*21) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7449). This variant is also known as 1407delC. This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9850045, 15121768, 16407375). It has also been observed to segregate with disease in related individuals. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2020

The c.418delC pathogenic mutation, located in coding exon 3 of the STK11 gene, results from a deletion of one nucleotide at position 418, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in several families diagnosed with Peutz-Jeghers Syndrome (Nakagawa et al. Hum Genet. 1998 Aug;103(2):168-72; Lim et al. Gastroenterology. 2004 Jun;126(7):1788-94; Amos et al. J Med Genet. 2004 May;41(5):327-33; de Leng et al. Clin Genet. 2007 Dec;72(6):568-73; Mehenni H et al. Dig Dis Sci, 2007 Aug;52:1924-33). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397518440; hg19: chr19-1219365;