Submissions for variant NM_003122.5(SPINK1):c.-147A>G

gnomAD frequency: 0.00075  dbSNP: rs779832256

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231104	SCV000287879	uncertain significance	Hereditary pancreatitis	2020-01-11	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant occurs in a non-coding region of the SPINK1 gene. It does not change the encoded amino acid sequence of the SPINK1 protein. This variant has been observed in an individual with pancreatic cancer who also carried another pathogenic variant (PMID: 28687971). Additionally, this variant has been observed in several individuals with chronic pancreatitis, as well as a control individual (PMID: 21610753, 17003641). ClinVar contains an entry for this variant (Variation ID: 239503). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant reduces promoter activity of SPINK1 and disrupts transcription factor binding in vitro (PMID: 21610753, 25792561, 28556356). However, the clinical significance of these findings is unknown.
Ambry Genetics	RCV000231104	SCV002699563	uncertain significance	Hereditary pancreatitis	2021-06-25	criteria provided, single submitter	clinical testing	The c.-147A>G variant is located in the 5' untranslated region (5’ UTR) of the SPINK1 gene. This variant results from an A to G substitution 147 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. The variant has been detected in multiple individuals with pancreatitis or pancreatic cancer (Keiles S et al. Pancreas, 2006 Oct;33:221-7; Boulling A et al. Eur. J. Hum. Genet., 2011 Oct;19:1066-73; Slavin TP et al. Fam Cancer, 2018 04;17:235-245). Functional studies showed that this alteration disrupts a putative HNF1-binding site and reduces the SPINK1 promoter activity (Boulling A et al. Eur. J. Hum. Genet., 2011 Oct;19:1066-73; Derikx MH et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2015 May;308:G779-84). However, it is unknown whether the reduced promoter activity is sufficient to cause disease. In addition, the variant has been detected in multiple unaffected individuals at our laboratory. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002487067	SCV002789868	uncertain significance	Hereditary pancreatitis; Tropical pancreatitis	2022-05-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114398	SCV003800514	uncertain significance	not provided	2023-11-28	criteria provided, single submitter	clinical testing	The SPINK1 c.-147A>G variant (rs779832256) is reported in the literature in individuals affected with pancreatitis or pancreatic cancer, but is also found in healthy controls (Boulling 2011, Derikx 2015, Keiles 2006, Slavin 2018). This variant is also reported in ClinVar (Variation ID: 239503), and is found in the general population with an overall allele frequency of 0.022% (7/31408 alleles) in the Genome Aggregation Database (v2.1.1). This variant occurs in the 5' untranslated region at a nucleotide that is weakly conserved, and in vitro reporter assays demonstrate reduced expression (Boulling 2011, Derikx 2015). However, whether reduced expression occurs in vivo or is sufficient for disease remains to be determined. Given available information, the clinical significance of this variant is uncertain at this time. References: Boulling A et al. Assessing the pathological relevance of SPINK1 promoter variants. Eur J Hum Genet. 2011 Oct;19(10):1066-73. PMID: 21610753. Derikx MH et al. Functional significance of SPINK1 promoter variants in chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2015 May 1;308(9):G779-84. PMID: 25792561. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Slavin TP et al. The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. Fam Cancer. 2018 Apr;17(2):235-245. PMID: 28687971.
Revvity Omics, Revvity	RCV003114398	SCV003820062	uncertain significance	not provided	2022-07-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463664	SCV004205538	uncertain significance	Tropical pancreatitis	2023-09-28	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV003114398	SCV005188657	uncertain significance	not provided		criteria provided, single submitter	not provided
GenomeConnect - Invitae Patient Insights Network	RCV000231104	SCV001749361	not provided	Hereditary pancreatitis		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV003929959	SCV004739176	likely benign	SPINK1-related disorder	2022-02-17	no assertion criteria provided	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).