19-1207038-G-T

Position:

• chr19-1207038-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_000455.5(STK11):​c.125G>T​(p.Arg42Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 7.62

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4161578).
• BP6: Variant 19-1207038-G-T is Benign according to our data. Variant chr19-1207038-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403781.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000958 (14/1461626) while in subpopulation EAS AF= 0.000353 (14/39700). AF 95% confidence interval is 0.000213. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.125G>T	p.Arg42Leu	missense_variant	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.125G>T	p.Arg42Leu	missense_variant	1/9		NP_001394184.1
STK11	NR_176325.1	n.1261G>T		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.125G>T	p.Arg42Leu	missense_variant	1/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.125G>T	p.Arg42Leu	missense_variant	1/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11379G>T		intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.125G>T		non_coding_transcript_exon_variant	1/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000604 AC: 15 AN: 248194 Hom.: 0 AF XY: 0.0000593 AC XY: 8 AN XY: 134982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000835

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74408

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000496 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 12, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces arginine with leucine at codon 42 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lung cancer (PMID: 17711506). This variant has been identified in 15/248194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2022	This missense variant replaces arginine with leucine at codon 42 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lung cancer (PMID: 17711506). This variant has been identified in 15/248194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2023	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2017

The p.Arg42Leu variant in STK11 has not been previously reported in the literatu re in individuals with Peutz-Jeghers syndrome, but has been reported in ClinVar (Variation ID 403781). This variant has also has been identified in 6/8552 of Ea st Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs148830698). Computational prediction tools and conservat ion analysis do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of the p.Arg42Leu variant is uncertain . -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30833958, 30287823, 24793789, 17711506) -

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.Arg42Leu variant was identified in a lung cancer and its corresponding normal tissue in a study looking at LKB1 mutations in a cohort of Japanese lung cancer patients (Onozato 2007). The variant was also identified in dbSNP (ID: rs148830698) as “With Uncertain significance allele”, in ClinVar (classified uncertain significance by Invitae, GeneDx, Ambry Genetics, Color Genomics and Laboratory for Molecular Medicine), Clinvitae (3x), Zhejiang University Database (12X), and was not identified in Cosmic, MutDB, LOVD 3.0, or Insight Hereditary Tumors Database. The variant was identified in control databases in 14 of 245526 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017); it was observed in the East Asian population in 14 of 17234 chromosomes (freq: 0.0008), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Arg42 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Leu to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;D;T
Eigen	Benign	0.059
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	.;D;.
REVEL	Uncertain	0.52
Sift	Benign	0.031	.;D;.
Sift4G	Uncertain	0.053	T;T;D
Polyphen		0.64	.;P;.
Vest4		0.69
MutPred		0.53		Loss of MoRF binding (P = 0.0591);Loss of MoRF binding (P = 0.0591);Loss of MoRF binding (P = 0.0591);
MVP		0.82
MPC		2.0
ClinPred		0.38	T
GERP RS		1.7
Varity_R		0.51
gMVP		0.91

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: rs148830698; hg19: chr19-1207037; COSMIC: COSV105889120; COSMIC: COSV105889120;