chr19-1223099-CGGCGCG-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The NM_000455.5(STK11):c.1037_1042delGCGCGG(p.Gly346_Ala347del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000186 in 1,610,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G346G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

STK11
NM_000455.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 6.51

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

familial pancreatic carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Peutz-Jeghers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000455.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.1037_1042delGCGCGG	p.Gly346_Ala347del	disruptive_inframe_deletion	Exon 8 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.1037_1042delGCGCGG	p.Gly346_Ala347del	disruptive_inframe_deletion	Exon 8 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.2304_2309delGCGCGG		non_coding_transcript_exon_variant	Exon 9 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.1037_1042delGCGCGG	p.Gly346_Ala347del	disruptive_inframe_deletion	Exon 8 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.1037_1042delGCGCGG	p.Gly346_Ala347del	disruptive_inframe_deletion	Exon 8 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.665_670delGCGCGG	p.Gly222_Ala223del	disruptive_inframe_deletion	Exon 10 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.862_867delGCGCGG		non_coding_transcript_exon_variant	Exon 9 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.862_867delGCGCGG		3_prime_UTR_variant	Exon 9 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000411

AC:

AN:

243400

AF XY:

0.00000754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000908

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458686

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

725416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

85788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52008

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111112

Other (OTH)

AF:

0.00

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1037_1042del, results in the deletion of 2 amino acid(s) of the STK11 protein (p.Gly346_Ala347del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 403793). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The STK11 c.1037_1042del; p.Gly346_Ala347del change deletes six nucleotides at position 1037-1042 resulting in an in-frame deletion of two amino acids in exon 8. This change has a maximum subpopulation frequency of 0.00091% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in at least one individual with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for hereditary breast and ovarian cancer risk assessment (PMID: 31742824). One individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified

Uncertain:2

Oct 06, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: STK11 c.1037_1042delGCGCGG (p.Gly346_Ala347del) results in an in-frame deletion that is predicted to remove 2 amino acids from the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 243400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1037_1042delGCGCGG has been observed in an individual(s) with a personal and/or family history of cancer related to Hereditary Breast And Ovarian Cancer Syndrome (Shao_2020). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31742824). ClinVar contains an entry for this variant (Variation ID: 403793). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1037_1042delGCGCGG variant (also known as p.G346_A347del) is located in coding exon 8 of the STK11 gene. This variant results from an in-frame GCGCGG deletion at nucleotide positions 1037 to 1042. This results in the in-frame deletion of a glycine and an alanine residue at codons 346 to 347. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). This amino acid region is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Apr 11, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Melanoma, cutaneous malignant, susceptibility to, 1

Uncertain:1

Mar 19, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.5

Mutation Taster

=111/89

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over