Description
The c.194+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 3 in the SPINK1 gene. This alteration occurs at the 3' terminus of the SPINK1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 16 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration was first reported in an individual with chronic pancreatitis (Witt H et al. Nat. Genet., 2000 Jun;25:213-6). A functional study found this mutation causes a splicing defect that significantly diminishes SPINK1 expression at the mRNA level and results in diminished trypsin inhibitor secretion (Kereszturi E et al. Gut, 2009 Apr;58:545-9). This mutation has been seen in individuals affected with idiopathic, familial, alcoholic, autoimmune and tropical chronic pancreatitis (Kereszturi E et al. Gut, 2009 Apr;58:545-9; Chang MC et al. J Gastroenterol Hepatol, 2014 Dec;29:2038-42; Cho SM et al. Ann Lab Med, 2016 Nov;36:555-60; Tang XY et al. Dig Liver Dis, 2020 02;52:143-148). This alteration has also been identified in individuals diagnosed with breast and/or pancreatic cancer (Yang X et al. PLoS One, 2015 Apr;10:e0125571; Boortalary T et al. Pancreas, 2018 Apr;47:e24-e25). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
