19-1223126-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000455.5(STK11):c.1062C>G(p.Phe354Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,611,676 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F354S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (49 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3 B:30 O:1
• Conservation: PhyloP100: -1.12

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05135572).
• BP6: Variant 19-1223126-C-G is Benign according to our data. Variant chr19-1223126-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 7461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1223126-C-G is described in Lovd as [Benign]. Variant chr19-1223126-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00396 (602/152154) while in subpopulation EAS AF= 0.0408 (211/5166). AF 95% confidence interval is 0.0363. There are 7 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 602 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.1062C>G	p.Phe354Leu	missense_variant	8/10	ENST00000326873.12
STK11	NM_001407255.1	c.1062C>G	p.Phe354Leu	missense_variant	8/9
STK11	NR_176325.1	n.2329C>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.1062C>G	p.Phe354Leu	missense_variant	8/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 152036 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.0407

Gnomad SAS AF: 0.00624

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00520 AC: 1274 AN: 245022 Hom.: 15 AF XY: 0.00519 AC XY: 693 AN XY: 133600

Gnomad AFR exome AF: 0.000930

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.0346

Gnomad SAS exome AF: 0.00241

Gnomad FIN exome AF: 0.000962

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00536

GnomAD4 exome AF: 0.00522 AC: 7623 AN: 1459522 Hom.: 49 Cov.: 31 AF XY: 0.00509 AC XY: 3696 AN XY: 725920

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00613

Gnomad4 EAS exome AF: 0.0393

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00457

Gnomad4 OTH exome AF: 0.00683

GnomAD4 genome AF: 0.00396 AC: 602 AN: 152154 Hom.: 7 Cov.: 33 AF XY: 0.00397 AC XY: 295 AN XY: 74374

Gnomad4 AFR AF: 0.000964

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.0408

Gnomad4 SAS AF: 0.00625

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00359

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00293 Hom.: 1

Bravo AF: 0.00435

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000930 AC: 4

ESP6500EA AF: 0.00528 AC: 45

ExAC AF: 0.00490 AC: 591

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00351

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:3 Benign:30 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1 Benign:10 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.7% (283/7750) East Asian chromosomes; ClinVar: 3 benign, 1 VUS -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Foundation Medicine, Inc.	-	- -

Peutz-Jeghers syndrome Uncertain:2 Benign:6

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	May 15, 2005	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 14, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -

Hereditary cancer-predisposing syndrome Benign:6

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 10, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 16, 2018	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	STK11: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 20393878, 24604241, 22995991, 20722467, 25333069, 20981092, 24728327, 15121768, 25751324, 26182300, 22942091, 27153395, 24928005, 28185117, 30092773, 30334930, 33250696) -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 06, 2019

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.Phe354Leu variant was identified in 20 of 1472 proband chromosomes (frequency: 0.014) from Korean, Japanese, Chinese and American individuals or families with Peutz-Jeghers disease, and Finnish, Korean, (French) Canadian, Portuguese, Italian, American individuals with CRC, high risk breast cancer, hereditary diffuse gastric cancer, pancreatic cancer, and medullary thyroid cancer; and was identified in 5 of 824 control chromosomes (frequency: 0.006) from healthy individuals (Yang 2010, Yajima 2013, Liu 2012, Huang 2015, Amos 2003, Launonen 2000, Guenard 2010, Hansford 2015, Jordan 2016, Simbolo 2014 ). Segregation of the variant with disease was not seen in 2 healthy family members of the PJ affected proband (Liu 2012), or an affected (breast cancer) family member of another proband (Guenard 2010). In a case report of a 76 year old female with papillary thyroid cancer with no clinical manifestations of PJ, the variant was identified to co-occur with a BRAF mutation (p.V600E, c.1799T>A) in the tumour (Shuanzeng 2016). In another study, the variant was identified in 2 Chinese patients with sporadic PJS, co-occurring with separate pathogenic STK11 mutations (del(exon1) and c.890G > A) (Tan 2017). Functional assays of the STK11 exons 8 and 9, localized to the C-terminal non-catalytic region, have shown that mutations within this region neither disrupt STK11 activity nor interfere with STK11 induced growth arrest, but do lessen STK11-mediated activation of the AMP-activated protein kinase (AMPK) and downstream signaling (Forcet 2005). The variant was also identified in dbSNP (ID: rs59912467) “With Likely benign, other allele”, Clinvar (classified as conflicting interpretations of pathogenicity: benign by GeneDx, Invitae, Ambry Genetics, Prevention Genetics, Counsyl, Laboratory for Molecular Medicine (Partners for HealthCare Personalized Medicine), Vantari Genetics, Color Genomics Inc; likely benign by Illumina; uncertain significance by Foundation Medicine Inc, OMIM, Pathway Genomics; and unclassified by ITMI), Clinvitae (4X), Cosmic 41X in tumours of the brain, breast, lung, large intestine, salivary gland and malignant melanoma), LOVD 3.0 (3X), Zhejiang Colon Cancer database (11X, all in combination with other multiple STK11 variants, including pathogenic variants: c.842delC, p.Pro281ArgfsX6/c.996G>A, p.Trp332X/c.465-1G>T); and was not identified in the Insight Hereditary Tumors Database. The variant was identified in control databases in 1363 (17 homozygous) of 273698 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following population at a frequency greater than 1%: East Asian in 658 (15 homozygous) of 18796 chromosomes (freq: 0.035). The p.Phe354 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 this variant meets our laboratory's criteria to be classified as benign -

Peutz-Jeghers syndrome;C0235974:Carcinoma of pancreas;C1336708:Germ cell tumor of testis;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.057
Dann	Benign	0.56
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.0069	A
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.57	T;T
Polyphen		0.062	.;B
Vest4		0.32
MutPred		0.79		Loss of stability (P = 0.0714);Loss of stability (P = 0.0714);
MVP		0.38
MPC		0.046
ClinPred		0.0031	T
GERP RS		-7.5
Varity_R		0.058
gMVP		0.19

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: rs59912467; hg19: chr19-1223125; COSMIC: COSV58819912; COSMIC: COSV58819912;