chr19-1226556-C-T
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
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
Consequence
NM_000455.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
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: 77AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000471 AC: 103AN: 218818Hom.: 0 AF XY: 0.000432 AC XY: 52AN XY: 120506
GnomAD4 exome AF: 0.000804 AC: 1164AN: 1447112Hom.: 1 Cov.: 31 AF XY: 0.000779 AC XY: 560AN XY: 718696
GnomAD4 genome AF: 0.000505 AC: 77AN: 152368Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:6
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | STK11: BP4 - |
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. - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 15, 2022 | - - |
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 28, 2015 | - - |
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 | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
not specified Uncertain:2Benign:4
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 | 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. - |
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+ | - | - - |
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 | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Peutz-Jeghers syndrome Uncertain:1Benign:5
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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 20, 2018 | - - |
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 | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 22, 2021 | - - |
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 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 12, 2017 | - - |
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 | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at