Submissions for variant NM_000455.5(STK11):c.1211C>T (p.Ser404Phe)

gnomAD frequency: 0.00051  dbSNP: rs200078204

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213035	SCV000149505	likely benign	not specified	2018-01-08	criteria provided, single submitter	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.
Ambry Genetics	RCV000115596	SCV000186069	likely benign	Hereditary cancer-predisposing syndrome	2018-12-07	criteria provided, single submitter	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.
Invitae	RCV000200450	SCV000253246	benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000589835	SCV000336816	uncertain significance	not provided	2015-10-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000200450	SCV000410748	benign	Peutz-Jeghers syndrome	2018-01-13	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000115596	SCV000537416	likely benign	Hereditary cancer-predisposing syndrome	2015-11-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213035	SCV000540468	uncertain significance	not specified	2016-12-02	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213035	SCV000602211	benign	not specified	2019-10-04	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115596	SCV000679745	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589835	SCV000696707	benign	not provided	2017-07-06	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000200450	SCV000786088	uncertain significance	Peutz-Jeghers syndrome	2018-02-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891608	SCV000806071	uncertain significance	STK11-related disorder	2024-01-10	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589835	SCV000884614	likely benign	not provided	2022-09-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000200450	SCV001140949	likely benign	Peutz-Jeghers syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589835	SCV001151583	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	STK11: BP4
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589835	SCV002009164	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000200450	SCV002057332	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000213035	SCV002066145	likely benign	not specified	2022-01-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115596	SCV002531658	likely benign	Hereditary cancer-predisposing syndrome	2021-07-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213035	SCV002552040	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149797	SCV003838540	uncertain significance	Breast and/or ovarian cancer	2023-05-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200450	SCV004017981	likely benign	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004689610	SCV005184340	likely benign	Hereditary breast ovarian cancer syndrome	2024-05-03	criteria provided, single submitter	curation	Frequently found in patients without signs of PJS; According to the ACMG SVI adaptation criteria we chose this criterion: BS1 (strong benign): AC:77 AF:0.000505747 hom:0 het:77 popmax:NFE popmax AF:0.000867162 popmax AC:59 popmax faf95:0.000689550 significantly greater than the maximum expected allele frequency for a pathogenic STK11 variant of 0.0000063 FLOSSIES num AFR:0 num EUR:10
Center of Medical Genetics and Primary Health Care	RCV001269488	SCV001449141	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589835	SCV001549584	likely benign	not provided		no assertion criteria provided	clinical testing	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.
Clinical Genetics, Academic Medical Center	RCV000589835	SCV001920164	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000213035	SCV001957129	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000589835	SCV002035160	likely benign	not provided		no assertion criteria provided	clinical testing