19-1207009-C-G

Position:

• chr19-1207009-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000455.5(STK11):​c.96C>G​(p.Thr32Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,613,658 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 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.764

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 19-1207009-C-G is Benign according to our data. Variant chr19-1207009-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 135930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1207009-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.764 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000986 (15/152138) while in subpopulation EAS AF= 0.00291 (15/5162). AF 95% confidence interval is 0.00179. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.96C>G	p.Thr32Thr	synonymous_variant	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.96C>G	p.Thr32Thr	synonymous_variant	1/9		NP_001394184.1
STK11	NR_176325.1	n.1232C>G		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.96C>G	p.Thr32Thr	synonymous_variant	1/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.96C>G	p.Thr32Thr	synonymous_variant	1/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11408C>G		intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.96C>G		non_coding_transcript_exon_variant	1/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000295 AC: 73 AN: 247554 Hom.: 0 AF XY: 0.000245 AC XY: 33 AN XY: 134724

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00390

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000239 AC: 349 AN: 1461520 Hom.: 2 Cov.: 31 AF XY: 0.000241 AC XY: 175 AN XY: 727040

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00809

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 14, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
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	Counsyl	Nov 23, 2015	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2014	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, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2018	Variant summary: STK11 c.96C>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.00028 in 275788 control chromosomes (gnomAD). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 624-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in population(s) of East Asian origin. The variant, c.96C>G, has been reported in the literature in individuals affected with mucinous MDA, breast cancer, and small-intestinal cancer (Kuragaki_2003, Lee_2017, Nakagawa_1999). Nakagawa_1999 indicates that the variant was only present in the tumor sample and not germline. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 15, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 02, 2016	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

STK11: BP4, BP7, BS1 -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.Thr32= variant was identified in the literature as a somatic variant in adenocarcinoma of the small intestine or uterine cervix in 2 Japanese patients (Nakagawa_1999_10429655, Kuragaki_2003_12533684). The variant was also identified in dbSNP (ID: rs79175212) as “With other allele”, ClinVar and Clinvitae (3x classified as benign by Invitae, GeneDx, Quest Diagnostics; 2x classified as likely benign by Ambry Genetics, Counsyl), COSMIC (2x confirmed somatic in the cases cited above), and the Zhejiang Colon Cancer Database (1x classified as probably no pathogenicity). The variant was not identified in MutDB, LOVD 3.0, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 78 of 275788 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23862 chromosomes (freq: 0.00004), “Other” in 1 of 6412 chromosomes (freq: 0.0002), Latino in 1 of 34378 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 125910 chromosomes (freq: 0.000008), East Asian in 74 of 18852 chromosomes (freq: 0.004); it was not observed in the Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr32= 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. In addition, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.86

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: rs79175212; hg19: chr19-1207008; COSMIC: COSV58820499; COSMIC: COSV58820499;