19-1223104-CGGACGA-CGGACGAGGACGA

Position:

• chr19-1223104-CGGACGA-CGGACGAGGACGA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_000455.5(STK11):​c.1051_1056dupGAGGAC​(p.Glu351_Asp352dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: STK11 NM_000455.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.978

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_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000455.5.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.1051_1056dupGAGGAC	p.Glu351_Asp352dup	conservative_inframe_insertion	8/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.1051_1056dupGAGGAC	p.Glu351_Asp352dup	conservative_inframe_insertion	8/9		NP_001394184.1
STK11	NR_176325.1	n.2318_2323dupGAGGAC		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1051_1056dupGAGGAC	p.Glu351_Asp352dup	conservative_inframe_insertion	8/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.1051_1056dupGAGGAC	p.Glu351_Asp352dup	conservative_inframe_insertion	8/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.679_684dupGAGGAC	p.Glu227_Asp228dup	conservative_inframe_insertion	10/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 243968 Hom.: 0 AF XY: 0.00000752 AC XY: 1 AN XY: 132998

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459018 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725606

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2021

In-frame insertion of 2 amino acids; Not observed at significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28900777) -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.Glu351_Asp352dup variant was not identified in the literature nor was it identified in the dbSNP, Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database, databases. The variant was identified in ClinVar (classified uncertain significance by GeneDx), Clinvitae (1x), and in control databases in 1 of 241680 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017) in the European (Non-Finnish) population in 1 of 109618 chromosomes (freq: 0.000009), while not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. This variant is an in-frame deletion resulting in the insertion of 2 residues (a glutamic acid (Glu) and aspartic (Asp) residue) at codon 352; the impact of this alteration on STK11 protein function is not known. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2023

The c.1051_1056dupGAGGAC variant (also known as p.E351_D352dup), located in coding exon 8 of the STK11 gene, results from an in-frame duplication of GAGGAC at nucleotide positions 1051 to 1056. This results in the duplication of 2 extra residues (ED) between codons 351 and 352. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Peutz-Jeghers syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2023

This variant, c.1051_1056dup, results in the insertion of 2 amino acid(s) of the STK11 protein (p.Glu351_Asp352dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individual(s) with ovarian cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 422813). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

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: rs762810203; hg19: chr19-1223103;