Submissions for variant NM_000455.5(STK11):c.842dup (p.Leu282fs)

dbSNP: rs121913321

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000474843	SCV000541102	pathogenic	Peutz-Jeghers syndrome	2023-11-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu282Alafs*3) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9760200, 16287113). ClinVar contains an entry for this variant (Variation ID: 403750). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492505	SCV000580906	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	The c.842dupC pathogenic mutation, located in coding exon 6 of the STK11 gene, results from a duplication of C at nucleotide position 842, causing a translational frameshift with a predicted alternate stop codon (p.L282Afs*3). This pathogenic mutation has been detected in numerous unrelated families with PJS (Nakagawa H et al. Hum Genet. 1998 Aug;103:168-72; Schumacher V et al. J Med Genet. 2005 May;42:428-35; Aretz S et al. Hum Mutat. 2005 Dec;26:513-9; Launonen V. Hum Mutat. 2005 Oct;26:291-7; Dai L et al. Dig Dis Sci. 2014 Aug;59:1856-61; Wu BD et al. Biomed Res Int. 2020 May;2020:9159315). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001566266	SCV001789761	pathogenic	not provided	2020-03-23	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32462036, 30092773, 9760200, 30689838, 28152038)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000474843	SCV001983473	pathogenic	Peutz-Jeghers syndrome	2021-09-30	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.842dupC (p.Leu282AlafsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Peutz-Jeghers Syndrome in HGMD. The variant allele was found at a frequency of 4.1e-06 in 241672 control chromosomes. c.842dupC has been reported in the literature in individuals affected with Peutz-Jeghers Syndrome (example, Nakagawa_1998, and Aretz_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000474843	SCV002057380	pathogenic	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing