chr19-1221265-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000455.5(STK11):c.787T>C(p.Leu263Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,314 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

STK11
NM_000455.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: 0.839

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 19-1221265-T-C is Benign according to our data. Variant chr19-1221265-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 139335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1221265-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.839 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000092 (14/152202) while in subpopulation NFE AF= 0.000206 (14/68024). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.787T>C	p.Leu263Leu	synonymous_variant	Exon 6 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.787T>C	p.Leu263Leu	synonymous_variant	Exon 6 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.2054T>C		non_coding_transcript_exon_variant	Exon 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.787T>C	p.Leu263Leu	synonymous_variant	Exon 6 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.787T>C	p.Leu263Leu	synonymous_variant	Exon 6 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.415T>C	p.Leu139Leu	synonymous_variant	Exon 8 of 12	3		ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000170

AC:

AN:

247226

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

134676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000703

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000242

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1460112

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

726306

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000249

Gnomad4 NFE exome

AF:

0.000185

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000110

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 11, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STK11: BP4, BP7 -

Hereditary cancer-predisposing syndrome

Benign:6

Jul 12, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 04, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 08, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4, BP7 c.787T>C, located in exon 6 of the STK11 gene, is predicted to result in no amino acid change, p.(Leu263=)(BP7). This variant is found in 34/117196, with a filter allele frequency of 0.019% at 99% confidence in the gnomAD v2.1.1 database (European non-Finnish non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing (BP4). To our knowledge, neither relevant clinical data nor functional studies have been reported for this variant This variant has been reported in the ClinVar database (7x benign, 16x likely benign) and in the LOVD database (5x likely benign). Based on currently available information, the variant c.787T>C is classified as a likely benign variant according to ACMG guidelines. -

Aug 10, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Peutz-Jeghers syndrome

Benign:6

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2015

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Apr 24, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Sep 21, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

STK11-related disorder

Benign:1

Jul 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STK11 p.Leu263= variant was not identified in the literature. The variant was identified in dbSNP (rs372378119) as â€šÃ„Ãºwith other alleleâ€šÃ„Ã¹, ClinVar (classified as likely benign by Color, Ambry Genetics, Counsyl, Quest Diagnostics and True Health Diagnostics and benign by Invitae and GeneDx) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 52 of 278,592 chromosomes at a frequency of 0.000187 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 7 of 10,250 chromosomes (freq: 0.0007), European in 36 of 127,104 chromosomes (freq: 0.0003), Other in 2 of 7086 chromosomes (freq: 0.0003), Finnish in 5 of 24,994 chromosomes (freq: 0.0002), South Asian in 2 of 30,470 chromosomes (freq: 0.00007), while the variant was not observed in the African, Latino and East Asian populations. The p.Leu263= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.5

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over