NM_000455.5:c.795G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000455.5(STK11):c.795G>A(p.Glu265Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000769 in 1,611,936 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 2 hom. )

Consequence

STK11
NM_000455.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.58

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 19-1221273-G-A is Benign according to our data. Variant chr19-1221273-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 182885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1221273-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000657 (10/152220) while in subpopulation SAS AF= 0.000828 (4/4832). AF 95% confidence interval is 0.000282. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.795G>A	p.Glu265Glu	synonymous_variant	Exon 6 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.795G>A	p.Glu265Glu	synonymous_variant	Exon 6 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.2062G>A		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.795G>A	p.Glu265Glu	synonymous_variant	Exon 6 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.795G>A	p.Glu265Glu	synonymous_variant	Exon 6 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.423G>A	p.Glu141Glu	synonymous_variant	Exon 8 of 12	3		ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

246466

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

134254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000758

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.0000781

AC:

114

AN:

1459716

Hom.:

Cov.:

AF XY:

0.0000964

AC XY:

AN XY:

726052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000651

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Benign:7

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 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

- -

Jun 01, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STK11: BP4, BP7 -

Oct 24, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Mar 06, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 17, 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. -

not specified

Benign:2

Jul 11, 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. -

Jan 01, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Sep 26, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial ovarian cancer

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STK11 p.Glu265= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs730881963) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified as benign by GeneDx and likely benign by Ambry Genetics, Invitae and Counsyl), Clinvitae (3x), and in control databases in 50 (1 homozygous) of 275192 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include, other in 4 of 6416 chromosomes (freq. 0.0006), Latino in 18 (1 homozygous) of 34300 chromosomes (freq. 0.0005), European Non-Finnish in 5 of 125550 chromosomes (freq. 0.00004), and South Asian in 23 of 30524 chromosomes (freq. 0.0007); it was not seen in the African, Ashkenazi Jewish, European Finnish, and East Asian populations. The variant was identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.6359C>G/ p.Ser2120X), increasing the likelihood that the p.Glu265=variant does not have clinical significance.The p.Glu265= 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 outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

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