Submissions for variant NM_000455.5(STK11):c.825G>A (p.Pro275=)

gnomAD frequency: 0.00011  dbSNP: rs202011521

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213020	SCV000171890	benign	not specified	2013-12-31	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	RCV000129143	SCV000183864	benign	Hereditary cancer-predisposing syndrome	2016-06-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000200552	SCV000252702	benign	Peutz-Jeghers syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000200552	SCV000410745	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000129143	SCV000686692	likely benign	Hereditary cancer-predisposing syndrome	2015-08-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000213020	SCV000859447	likely benign	not specified	2018-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213020	SCV000888647	benign	not specified	2022-06-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000200552	SCV001140940	likely benign	Peutz-Jeghers syndrome	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000213020	SCV001160237	benign	not specified	2019-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213020	SCV001437322	benign	not specified	2020-09-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000200552	SCV002057284	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759361	SCV002063699	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	STK11: BP4, BP7
Sema4, Sema4	RCV000129143	SCV002526942	benign	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149875	SCV003838182	likely benign	Breast and/or ovarian cancer	2021-06-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213020	SCV004026953	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129143	SCV004228093	likely benign	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000759361	SCV001550964	likely benign	not provided		no assertion criteria provided	clinical testing	The STK11 p.Pro275= variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs202011521) as “With other allele”, ClinVar (as benign by GeneDx, Ambry Genetics, and Invitae, as likely benign by Quest Diagnostics and Color Genomics, and as uncertain significance by Ilumina), and Clinvitae (with conflicting interpretations of pathogenicity). The variant was identified in control databases in 53 of 271464 chromosomes at a frequency of 0.000195 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 23358 chromosomes (freq: 0.000086), Other in 3 of 6346 chromosomes (freq: 0.000473), Latino in 8 of 33978 chromosomes (freq: 0.000235), European (Non-Finnish) in 13 of 123704 chromosomes (freq: 0.000105), Ashkenazi Jewish in 27 of 9978 chromosomes (freq: 0.002706); it was not observed in the East Asian, European (Finnish), and South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing with a possible creation of a cryptic splice site; this is not very predictive of pathogenicity. The p.Pro275= 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 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.