Submissions for variant NM_001379610.1(SPINK1):c.101A>G (p.Asn34Ser)

gnomAD frequency: 0.00797  dbSNP: rs17107315

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000119030	SCV000053127	pathogenic	Hereditary pancreatitis	2020-06-08	criteria provided, single submitter	clinical testing	SPINK1 c.101A>G (p.Asn34Ser) results in a conservative amino acid change located in the Kazal domain (IPR002350) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.009 in 254072 control chromosomes (gnomAD and publication data), including 20 homozygotes. This frequency is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SPINK1 variant. However, this variant is a well-reported pathogenic risk factor that is known to be relatively frequent in the general population. Multiple studies have identified the variant in the compound heterozygous and homozygous state in numerous patients with chronic pancreatitis (example, Witt_2000, Chandak_2002, Rosendahl_2012, Pelaez-Luna_2014). Large association studies have been performed that suggest a strong association between the variant and disease, with odds ratios ranging from 10 to over 50 (example, Chen_2009, Witt_2000). However, experimental data reported that the trypsin inhibitory activity of the variant protein was preserved (> 90% of normal) and there was no significant difference in mRNA expression or splicing compared to wild-type (Kuwata_2002, Kiraly_2007, Boulling_2012). Although it has been proposed that other cis-linked variant(s) might be responsible for the observed increased pancreatitis risk conferred by the N34S haplotype, studies reporting a causative role of this variant within its associated haplotype have also been reported (Boulling_2012, Boulling_2017, Kereszturi_2017). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (n=3), Pathogenic (n=4) or Risk factor (n=2)). Based on the evidence outlined above, the variant was classified as a pathogenic risk factor for predisposition to Chronic Pancreatitis.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119030	SCV000252902	association	Hereditary pancreatitis	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the SPINK1 protein (p.Asn34Ser). This variant is present in population databases (rs17107315, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. This variant is reported as heterozygous in ~12% of individuals affected with chronic pancreatitis and in ~1.9% of unaffected controls (PMID: 17466744). Based on this data, this variant is expected to confer ~6-12 fold increased risk for chronic pancreatitis in heterozygous carriers. Homozygous individuals have been reported in approximately 3-5% of individuals with chronic pancreatitis (PMID: 23951356, 10835640), ~0.015% of the general population (ExAC), and in no unaffected controls to date (reviewed in PMID: 17466744). Although homozygous individuals are presumed to have at least twice the risk of heterozygous carriers, an accurate odds ratio can not be calculated due to the small number of homozygous individuals in the general population. ClinVar contains an entry for this variant (Variation ID: 13760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Multiple studies have failed to demonstrate that this Asn34Ser missense change disrupts any known function of the SPINK1 protein (PMID: 12483248, 17568390, 17525091). In summary, this variant is a missense change that does not affect any known function of the SPINK1 protein function. While this variant is associated with a significant risk for developing chronic pancreatitis, in the absence of a deleterious protein effect it remains uncertain whether this variant directly contributes to disease or if it may be linked to an undiscovered mutation (PMID: 19299380). Therefore, it has been classified as an Increased Risk Allele.
GeneDx	RCV000656981	SCV000577224	uncertain significance	not provided	2017-10-31	criteria provided, single submitter	clinical testing	This variant is denoted SPINK1 c.101A>G at the cDNA level, p.Asn34Ser (N34S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant is associated with an increased risk of pancreatitis when present with other genetic or environmental risk factors (Witt 2000, Diaconu 2009, Masamune 2011, LaSaito 2016). In a meta-analysis, this variant was identified in the heterozygous state in 274/2927 Caucasian pancreatitis cases and 79/5298 controls (OR=6.82), and in the homozygous state in 54/2981 cases and 1/5299 controls (OR=97.74) (Di Leo 2017). Functional studies of SPINK1 N34S demonstrated no change in trypsin inhibition or binding activity, suggesting that SPINK1 N34S on its own is insufficient to cause pancreatitis (Kuwata 2002, Boulling 2007). SPINK1 Asn34Ser is the most common SPINK1 pancreatitis risk allele, with an allele frequency of 0.97% (590/60648) and 2.2% (332/15160) in individuals of European (non-Finnish) and South Asian ancestry, respectively, in large population cohorts (Lek 2016). This variant is located in the Kazal-like domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, we consider SPINK1 Asn34Ser to be a risk allele.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656981	SCV000605239	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	The SPINK1 c.101A>G; p.Asn34Ser variant (rs17107315) has been detected at a statistically significant increased frequency in individuals with pancreatitis as compared to the general population (Aoun 2010, Masson 2013, Rosendahl 2013), co-segregating with pancreatitis patients in multiple families (Wu 2022). This variant and its associated haplotype is a risk factor for developing pancreatitis when combined with an additional pathogenic SPINK1 variant on the opposite chromosome, a severe pathogenic CFTR gene variant, or a pathogenic CTRC gene variant (Boulling 2017, Rosendahl 2013, Zou 2018). The p.Asn34Ser variant is reported in ClinVar (Variation ID: 13760). This variant is found in the general population with an overall allele frequency of 0.9% (2537/281004 alleles, 23 homozygotes) in the Genome Aggregation Database. The asparagine at codon 34 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.199). Based on this variant's strong association with pancreatitis, we consider it pathogenic. References: Aoun E et al. SPINK1 N34S is strongly associated with recurrent acute pancreatitis but is not a risk factor for the first or sentinel acute pancreatitis event. Am J Gastroenterol. 2010 105(2):446-51. PMID: 19888199. Boulling A et al. Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype. Hum Mutat. 2017 Aug;38(8):1014-1024. PMID: 28556356. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. PMID: 23951356. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 62(4):582-92. PMID: 22427236. Wu D et al. The clinical and genetic features of hereditary pancreatitis in South Australia. Med J Aust. 2022 Jun 20;216(11):578-582. PMID: 35578795. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000119030	SCV000782314	pathogenic	Hereditary pancreatitis	2016-11-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000119030	SCV000967008	risk factor	Hereditary pancreatitis	2021-03-12	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Mendelics	RCV000119030	SCV001136991	uncertain significance	Hereditary pancreatitis	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000119030	SCV001169814	pathogenic	Hereditary pancreatitis	2023-08-21	criteria provided, single submitter	clinical testing	The c.101A>G (p.N34S) alteration is located in exon 3 (coding exon 3) of the SPINK1 gene. This alteration results from an A to G substitution at nucleotide position 101, causing the asparagine (N) at amino acid position 34 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.903% (2537/281004) total alleles studied. The highest observed frequency was 1.975% (602/30476) of South Asian alleles. This mutation has been observed in heterozygous and homozygous states in individuals with chronic pancreatitis (Witt, 2000). In case control studies, p.N34S has has been associated with a significant odds ratio for both acute pancreatitis and chronic pancreatitis (O'Reilly, 2008; Rosendahl, 2013). Heterozygous p.N34S confers an increased risk, while homozygous p.N34S is considered to be disease-causing (Masson, 2013). This amino acid position is poorly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000656981	SCV001248360	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SPINK1: PP1:Strong, PS1, PS4, PP4:Moderate, BP4
Illumina Laboratory Services, Illumina	RCV000119030	SCV001316926	uncertain significance	Hereditary pancreatitis	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000119030	SCV001366803	pathogenic	Hereditary pancreatitis	2019-08-23	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: BS1,PS4,PS1. This variant was detected in homozygous state.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258230	SCV001435136	likely benign	Finnish congenital nephrotic syndrome		criteria provided, single submitter	research	The p.Asn34Ser variant in SPINK1 has been reported in 12 heterozygous and 6 homozygous individuals with chronic pancreatitis (PMID: 10835640). It has also been identified in >0.1% of chromosomes, including 9 homozygotes, by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that this variant does not impact protein function (PMID: 12483248, 17568390, 17525091). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant chronic pancreatitis.
Baylor Genetics	RCV000119030	SCV001522929	pathogenic	Hereditary pancreatitis	2020-11-17	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Undiagnosed Diseases Network, NIH	RCV000119030	SCV001736855	pathogenic	Hereditary pancreatitis	2020-11-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000119030	SCV002505611	established risk allele	Hereditary pancreatitis	2022-03-08	criteria provided, single submitter	clinical testing	One of the most important CP-associated heritable risk factors (odds ratio (OR) = 10.90; 95% confidence interval 7.56–15.72). No functional data support pathogenic effect (expression, secretion or trypsin inhibitory activity of SPINK1). Linked with SNP rs142703147:C>A (c.-4141G>T) in this individual (this variant disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module (CRM). Co-transfection transactivation experiments have demonstrated that this variant leads to reduced gene expression. Two pancreatic cancer cell lines heterozygous for the SPINK1 N34S haplotype exhibited reduced expression of the variant allele and suggested that c.-4141G>T might be a candidate causal variant. See Pu et al., 2021, PMID: 34828289
Sema4, Sema4	RCV000119030	SCV002535378	pathogenic	Hereditary pancreatitis	2021-05-24	criteria provided, single submitter	curation
3billion	RCV002283443	SCV002572766	pathogenic	Tropical pancreatitis	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.903%. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SPINK1 -related disorder (ClinVar ID: VCV000013760 / PMID: 10835640 / 3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22427236). It has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11950815 , 12187509). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV002283443	SCV003836313	likely pathogenic	Tropical pancreatitis	2022-03-17	criteria provided, single submitter	clinical testing
Eurofins-Biomnis	RCV000119030	SCV003935033	likely pathogenic	Hereditary pancreatitis	2022-12-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000119030	SCV004048160	uncertain significance	Hereditary pancreatitis	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.6700C>T (p.Pro2234Ser) in APC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro2234Ser variant has allele frequency 0.0008% in gnomAD Exomes. This variant has been sumitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and Mutation Taster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid in APC gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 2234 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance.
OMIM	RCV000014768	SCV000035023	uncertain significance	Pancreatitis, chronic, susceptibility to	2002-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000119030	SCV000153734	not provided	Hereditary pancreatitis		no assertion provided	literature only
GenomeConnect, ClinGen	RCV000119030	SCV000607175	not provided	Hereditary pancreatitis		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV002468556	SCV002764629	likely risk allele	Pancreatitis		no assertion criteria provided	research	The SPINK1 c.101A>G (p.Asn34Ser) variant is a commonly reported risk variant associated with pancreatitis and has been reported in >300 affected individuals, as well as in >100 unaffected controls (Di Leo_2017_PMID: 28546062; Diaconu_2009_PMID: 19565042; Masamune_2011_PMID: 21303407; Chandak_2002_PMID: 12011155; Rosendahl_2013_PMID: 22427236; Witt_2000_PMID: 10835640). In a large meta-analysis, this variant has a reported odds ratio of 9.695 (CI 95% 7.931–11.851) in pancreatitis cases vs controls (Di Leo_2017_PMID: 28546062). The variant was identified in dbSNP (ID: rs17107315) and ClinVar (classified as pathogenic by Ambry Genetics and 8 other submitters; as uncertain significance by GeneDx and 4 other submitters; as "risk factor" by Laboratory for Molecular Medicine; and as "association" by Invitae). The variant was identified in control databases in 2537 of 281004 chromosomes (23 homozygous) at a frequency of 0.009028, and was observed at the highest frequency in the South Asian population in 602 of 30476 chromosomes (freq: 0.01975) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Asn34 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein. Three in vitro functional studies have demonstrated that this variant does not affect protein expression or trypsin inhibitory activity (Kuwata_2002_PMID: 12483248; Boulling_2007_PMID: 17568390; Kiraly_2007_PMID: 17525091). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. However, this variant may act as a risk factor for pancreatitis.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000119030	SCV003932346	likely risk allele	Hereditary pancreatitis	2023-06-15	no assertion criteria provided	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the SPINK1 protein (p.Asn34Ser). This variant is present in population databases (rs17107315, gnomAD 2.0%). This variant is reported as heterozygous in ~12% of individuals affected with chronic pancreatitis and in ~1.9% of unaffected controls (PMID: 17466744). Based on this data, this variant is expected to confer ~6-12 fold increased risk for chronic pancreatitis in heterozygous carriers. Homozygous individuals have been reported in approximately 3-5% of individuals with chronic pancreatitis (PMID: 23951356, 10835640), ~0.015% of the general population (ExAC), and in no unaffected controls to date (reviewed in PMID: 17466744). Although homozygous individuals are presumed to have at least twice the risk of heterozygous carriers, an accurate odds ratio can not be calculated due to the small number of homozygous individuals in the general population. ClinVar contains an entry for this variant (Variation ID: 13760). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Multiple studies have failed to demonstrate that this Asn34Ser missense change disrupts any known function of the SPINK1 protein (PMID: 12483248, 17568390, 17525091). In summary, this variant is a missense change that does not affect any known function of the SPINK1 protein function. While this variant is associated with a significant risk for developing chronic pancreatitis, in the absence of a deleterious protein effect it remains uncertain whether this variant directly contributes to disease or if it may be linked to an undiscovered mutation (PMID: 19299380). Therefore, it has been classified as an Increased Risk Allele.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000119030	SCV004014855	established risk allele	Hereditary pancreatitis	2023-07-20	no assertion criteria provided	case-control
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000119030	SCV004101105	pathogenic	Hereditary pancreatitis	2023-11-02	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000119030	SCV004228974	not provided	Hereditary pancreatitis		no assertion provided	phenotyping only	Variant interpreted as Established risk allele and reported on 01-31-2020 by Lab 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.