ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.464+10C>T (rs587782445)

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Total submissions: 10
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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 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000196091 SCV000489702 likely benign Peutz-Jeghers syndrome 2016-11-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507764 SCV000602224 likely benign not specified 2016-11-03 criteria provided, single submitter clinical testing
Color Health, Inc 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 RCV000590338 SCV000889859 benign not provided 2018-06-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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
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.

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