rs1131690938

chr19-1220389-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000455.5(STK11):c.481A>T(p.Ile161Phe) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I161L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.32

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1220389-A-T is Pathogenic according to our data. Variant chr19-1220389-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428774.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.481A>T	p.Ile161Phe	missense_variant	4/10	ENST00000326873.12
STK11	NM_001407255.1	c.481A>T	p.Ile161Phe	missense_variant	4/9
STK11	NR_176325.1	n.1748A>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.481A>T	p.Ile161Phe	missense_variant	4/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2017

This variant is denoted STK11 c.481A>T at the cDNA level, p.Ile161Phe (I161F) at the protein level,and results in the change of an Isoleucine to a Phenylalanine (ATT>TTT). This variant has been observed in at leastone family meeting clinical diagnostic criteria of Peutz-Jeghers Syndrome (Borun 2013). STK11 Ile161Phe was notobserved in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acidsubstitution. STK11 Ile161Phe occurs at a position where amino acids with properties similar to Isoleucine aretolerated across species and is located within the Protein kinase domain (UniProt). In silico analyses are inconsistentregarding the effect this variant may have on protein structure and function. Based on the currently available evidenceand internal data, we consider STK11 Ile161Phe to be a likely pathogenic variant -

Peutz-Jeghers syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2016

The p.I161F variant (also known as c.481A>T), located in coding exon 4 of the STK11 gene, results from an A to T substitution at nucleotide position 481. The isoleucine at codon 161 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was detected in one patient meeting diagnostic criteria for Peutz-Jeghers syndrome (PJS), however clinical details were limited (Borun P et al. BMC Med. Genet., 2013 May;14:58). 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 6316 samples (12632 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. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.13	T;T;D
Polyphen		0.54	.;P;.
Vest4		0.88
MutPred		0.68		Loss of stability (P = 0.1151);Loss of stability (P = 0.1151);.;
MVP		0.66
MPC		2.1
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.58
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1131690938; hg19: chr19-1220388; COSMIC: COSV58828738; COSMIC: COSV58828738;