Submissions for variant NM_000455.5(STK11):c.464+10C>T

gnomAD frequency: 0.00003  dbSNP: rs587782445

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131511	SCV000186504	likely benign	Hereditary cancer-predisposing syndrome	2014-01-23	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	RCV000196091	SCV000252700	benign	Peutz-Jeghers syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000196091	SCV000489702	likely benign	Peutz-Jeghers syndrome	2016-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131511	SCV000686651	likely benign	Hereditary cancer-predisposing syndrome	2016-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590338	SCV000696719	benign	not provided	2017-06-09	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.464+10C>T variant involves the alteration of a non-conserved intronic nucleotide and 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 9/36576 control chromosomes (1 homozygote), predominantly in the South Asian cohort at a frequency of 0.00069 (6/8690, 1 homozygote). This frequency is about 110 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this is likely a benign polymorphism found primarily population(s) of South Asian origin. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507764	SCV000889859	benign	not specified	2018-06-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000196091	SCV001280941	benign	Peutz-Jeghers syndrome	2019-03-05	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000590338	SCV001827743	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000196091	SCV002057408	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492513	SCV002795533	likely benign	Carcinoma of pancreas; Peutz-Jeghers syndrome; Melanoma, cutaneous malignant, susceptibility to, 1; Germ cell tumor of testis	2021-11-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000196091	SCV004015573	benign	Peutz-Jeghers syndrome	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000196091	SCV004018005	likely benign	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492625	SCV004239723	likely benign	Breast and/or ovarian cancer	2023-04-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945149	SCV004763947	likely benign	STK11-related condition	2020-03-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000507764	SCV001548675	benign	not specified		no assertion criteria provided	clinical testing	The STK11 c.464+10C>T variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang University Database, or the Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs587782445) as "With other allele", and in ClinVar (6x as Benign by Invitae and Laboratory Corporation of America and Likely benign by Ambry Genetics, Counsyl, Quest and Colour Genomics). The variant was identified in control databases in 22 of 201784 chromosomes (1 homozygous) at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: South Asian in 11 of 24022 chromosomes (freq: 0.000458), African in 2 of 17856 chromosomes (freq: 0.0001), Other in 1 of 5152 chromosomes (freq: 0.0002), Latino in 3 of 27010 chromosomes (freq: 0.000111), European Non-Finnish in 1 of 86922 chromosomes (freq: 0.000012), Ashkenazi Jewish in 1 of 8794 chromosomes (freq: 0.000114), and East Asian in 3 of 13308 chromosomes (freq: 0.000225); it was not observed in the Finnish populations. Of note the conservative allelic frequency of variants pathogenic for Peutz-Jegher Syndrome is an order of magnitude lower than the prevalence of the variant in the South Asian population (0.00002 vs 0.0004). The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant was identified with a co-occurring pathogenic variant in the BRCA1 (c.895_896del) gene in the context of a HBOC referral, increasing the likelihood this variant may not have clinical significance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely benign.