Submissions for variant NM_000455.5(STK11):c.464+9G>A

gnomAD frequency: 0.00208  dbSNP: rs376313955

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213011	SCV000171885	benign	not specified	2014-03-26	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	RCV000131962	SCV000187019	likely benign	Hereditary cancer-predisposing syndrome	2013-08-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000198311	SCV000252701	benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000198311	SCV000410738	benign	Peutz-Jeghers syndrome	2018-01-12	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131962	SCV000576425	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131962	SCV000686656	benign	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587711	SCV000696720	benign	not provided	2016-05-03	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.464+9G>A variant affects a non-conserved intronic nucleotide not widely known to affect splicing. Mutation Taster predicts a benign outcome for this variant, and 4/5 Alamut algorithms predict no significant change to splicing. This variant was found in 39/36972 control chromosomes at a frequency of 0.0010549, which is about 190 times the maximal expected frequency of a pathogenic STK11 allele (0.0000056), suggesting this variant is benign. In addition, several clinical laboratories classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Additionally, the variant co-occurred with a pathogenic PMS2 variant (c.2186_2187delTC) in one internal specimen. Taken together, this variant was classified as benign.
Eurofins Ntd Llc (ga)	RCV000213011	SCV000859972	likely benign	not specified	2018-03-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587711	SCV000889860	benign	not provided	2022-02-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798430	SCV002042768	likely benign	Breast and/or ovarian cancer	2022-09-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000198311	SCV002057407	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131962	SCV002531701	benign	Hereditary cancer-predisposing syndrome	2020-10-22	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000198311	SCV004015570	benign	Peutz-Jeghers syndrome	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587711	SCV004700116	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	STK11: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003915279	SCV004737155	benign	STK11-related disorder	2019-11-19	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000213011	SCV000692045	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356286	SCV001551411	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 c.464+9G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs376313955) as "With other allele", in ClinVar (5x Benign by Invitae, GeneDx and three other submitters, 5x likely benign by Ambry Genetics and four other submitters), and in LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 165 of 203546 chromosomes at a frequency of 0.0008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 132 of 18030 chromosomes (freq: 0.007), Other in 4 of 5186 chromosomes (freq: 0.0008), Latino in 26 of 27178 chromosomes (freq: 0.001), European in 2 of 87470 chromosomes (freq: 0.00002) and East Asian in 1 of 13646 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.