19-1226556-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000455.5(STK11):c.1211C>T(p.Ser404Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,599,480 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. S404Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:20
• Conservation: PhyloP100: 1.47

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0695084).
• BP6: Variant 19-1226556-C-T is Benign according to our data. Variant chr19-1226556-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127700.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Uncertain_significance=7, Benign=4}. Variant chr19-1226556-C-T is described in Lovd as [Likely_benign]. Variant chr19-1226556-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000505 (77/152368) while in subpopulation NFE AF= 0.000867 (59/68030). AF 95% confidence interval is 0.00069. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.1211C>T	p.Ser404Phe	missense_variant	9/10	ENST00000326873.12
STK11	NR_176325.1	n.2478C>T		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.1211C>T	p.Ser404Phe	missense_variant	9/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000471 AC: 103 AN: 218818 Hom.: 0 AF XY: 0.000432 AC XY: 52 AN XY: 120506

Gnomad AFR exome AF: 0.0000829

Gnomad AMR exome AF: 0.000249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000890

Gnomad OTH exome AF: 0.000916

GnomAD4 exome AF: 0.000804 AC: 1164 AN: 1447112 Hom.: 1 Cov.: 31 AF XY: 0.000779 AC XY: 560 AN XY: 718696

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.000372

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000984

Gnomad4 OTH exome AF: 0.000569

GnomAD4 genome AF: 0.000505 AC: 77 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74502

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000578

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000611 AC: 5

ExAC AF: 0.000479 AC: 57

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:20

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:6

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The STK11 p.Ser404Phe variant was identified in 7 of 3890 proband chromosomes (frequency: 0.002) from Lebanese, German, and American individuals or families with breast cancer, hereditary breast cancer, CRC, or Lynch syndrome (Jalkh 2017, Tung 2016, Kraus 2014, Yurgelun 2015). In 1 proband with 3 family members diagnosed with breast cancer, exome sequencing identified the variant co-occurring with 2 other disease-causing mutations (BRCA1 c.G131T, p.C44F and SLX4 c.G421T, p.G141W) (Jalkh 2017). The variant was also identified in dbSNP (ID: rs200078204) “With other allele”, ClinVar (6x as likely benign by GeneDx, Ambry Genetics, Invitae, Illumina, Color Genomics and Quest Diagnostics Nichols Institute San Juan Capistrano and 2x as uncertain significance by EGL Genetic Diagnostics and Laboratory for Molecular Medicine), and LOVD 3.0 (2x). The variant was not identified in Cosmic, MutDB,Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database. The variant was identified in control databases in 106 of 245718 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was seen in the following populations: African in 4 of 20584 chromosomes (freq: 0.0002), Other in 3 of 5868 chromosomes (freq: 0.0005), Latino in 7 of 32154 chromosomes (freq: 0.0002), European Non-Finnish in 89 of 109936 chromosomes (freq: 0.0008), and South Asian in 3 of 27996 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser404Phe residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	STK11: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2017	Variant summary: The variant of interest, c.1211C>T (p.Ser404Phe) alters a conserved nucleotide with 2/4 in silico programs (SNPs&GO not captured here due to low reliability index), although these predictions have yet to be functionally assessed. The variant of interest was observed in a large, broad control datasets of ExAC and gnomAD with an allele frequency of 0.0009281 and 0.0004314 (52/56030 and 106/245718 chrs tested, respectively). These frequencies are significantly greater than the maximum expected allele frequency for a pathogenic STK11 variant of 0.0000063, therefore suggesting the variant of interest is benign. The variant of interest has been reported in multiple affected individuals with varying phenotypic information, including in probands from two unrelated families, where a known pathogenic variants were proven to be causative and segregated with desiase in affected family members (Yurgelun, 2017; Jalth, 2017). In aaddition, multiple clinical labs have classified this variant as "likely benign". Taking together, the variant of interest has been classified as Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Uncertain:2 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 04, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 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: This variant is present in ExAC with a MaxMAF of 0.160% (49 European alleles) and 0.08% in gnomAD (90 European alleles - too high for disease prevalence - highest estimates are 1/60,000). It is classified in ClinVar with 2 stars as Likely benign by 3 submitters (Invitae, Ambry, GeneDx). It has been reported in HGMD in 1 patient with Peutz-Jeghers syndrome and one with renal cell carcinoma. The amino acid is not conserved but no species have a Phe at this position. -

Peutz-Jeghers syndrome Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 14, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2018	This alteration is classified as likely 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. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 05, 2023

- -

STK11-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

The STK11 c.1211C>T variant is predicted to result in the amino acid substitution p.Ser404Phe. This variant has been reported in individuals with Peutz Jeghers syndrome, renal cell carcinoma and colorectal cancer (Sinagra et al. 2013. PubMed ID: 23993471; Yalniz et al. 2014. PubMed ID: 25179843; Kraus et al. 2015. PubMed ID: 25142776; Yurgelun et al. 2017. PubMed ID: 28135145). It has also been documented in individuals with breast cancer, and at least one of these patients had additional variants in different cancer-associated genes (Chong et al. 2014. PubMed ID: 24830819; Tung et al. 2016. PubMed ID: 26976419; Jalkh et al. 2017. PubMed ID: 28202063). This variant is reported in 0.087% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127700/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T;D
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
Sift4G	Uncertain	0.043	D;D
Polyphen		0.055	.;B
Vest4		0.77
MVP		0.42
MPC		0.047
ClinPred		0.028	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.16

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: rs200078204; hg19: chr19-1226555; COSMIC: COSV99289465; COSMIC: COSV99289465;