Submissions for variant NM_000455.5(STK11):c.615G>A (p.Ala205=)

gnomAD frequency: 0.00003  dbSNP: rs532889728

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213016	SCV000211684	benign	not specified	2014-06-09	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	RCV000160974	SCV000213651	likely benign	Hereditary cancer-predisposing syndrome	2015-03-12	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	RCV000229020	SCV000284870	likely benign	Peutz-Jeghers syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000229020	SCV000488658	likely benign	Peutz-Jeghers syndrome	2016-05-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160974	SCV000691530	likely benign	Hereditary cancer-predisposing syndrome	2019-12-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759355	SCV000888641	likely benign	not provided	2022-11-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000229020	SCV001284038	likely benign	Peutz-Jeghers syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213016	SCV001338171	likely benign	not specified	2020-02-22	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000160974	SCV001750213	likely benign	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	clinical testing	STK11:c.615G>A p.(Ala205=) variant was detected in 2 patients without Peutz-Jeghers phenotype. The variants is predicted to create a new acceptor splice site by in silico splicing tools. Functional RNA study has shown that the variant causes insignificant splicing aberration (PMID: 34439939). Therefore the variant was classified as likely benign (ACMG/AMP: BS3, BP5, PM2).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001731149	SCV001981605	likely benign	Hereditary breast ovarian cancer syndrome	2021-10-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000229020	SCV002057268	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213016	SCV002552018	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000229020	SCV004017959	benign	Peutz-Jeghers syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
All of Us Research Program, National Institutes of Health	RCV000229020	SCV004816388	likely benign	Peutz-Jeghers syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000229020	SCV001553312	likely benign	Peutz-Jeghers syndrome		no assertion criteria provided	clinical testing	The STK11 p.Ala205= variant was identified in 1 of 14102 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer and was not identified in 22482 control chromosomes from healthy individuals (Momozawa, 2018). The variant was also identified in dbSNP (ID: rs532889728) as “With other allele”, ClinVar (classified as benign by GeneDx, as likely benign by Ambry Genetics and Counsyl, and as uncertain significance by Invitae and Color Genomics), LOVD 3.0 (classified as uncertain significance). The variant was identified in control databases in 10 of 238092 chromosomes at a frequency of 0.000042 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 2 of 30902 chromosomes (freq: 0.000065), European Non-Finnish in 6 of 105662 chromosomes (freq: 0.000057), East Asian in 2 of 16486 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Ashkenazi Jewish, European Finnish, and South Asian populations. The variant has been observed in our laboratory in a patient with pancreatic cancer with an alternate molecular basis for disease (ATM c.1A>G). In a study of STK11 variants this variant was observed to demonstrate IHC stain intensity comparable to wild type (Pelak, 2013). The p.Ala205= 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. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% 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.