NM_001379610.1(SPINK1):c.194+2T>C AND Hereditary pancreatitis

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Jan 26, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000119031.36

Allele description [Variation Report for NM_001379610.1(SPINK1):c.194+2T>C]

NM_001379610.1(SPINK1):c.194+2T>C

Gene:

SPINK1:serine peptidase inhibitor Kazal type 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q32

Genomic location:

Preferred name:

NM_001379610.1(SPINK1):c.194+2T>C

Other names:

IVS3+2T>C

HGVS:

NC_000005.10:g.147828020A>G
NG_008356.2:g.16212T>C
NM_001354966.2:c.194+2T>C
NM_001379610.1:c.194+2T>CMANE SELECT
NM_003122.5:c.194+2T>C
NC_000005.9:g.147207583A>G
NM_003122.3:c.194+2T>C
NM_003122.4:c.194+2T>C

Links:

dbSNP: rs148954387

NCBI 1000 Genomes Browser:

rs148954387

Molecular consequence:

NM_001354966.2:c.194+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001379610.1:c.194+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_003122.5:c.194+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: Hereditary pancreatitis (PCTT)
Synonyms:: Hereditary chronic pancreatitis
Identifiers:: MONDO: MONDO:0008185; MedGen: C0238339; Orphanet: 676; OMIM: 167800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000153735	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000253884	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15980664, 23017645, 26632706, 18978175, 26719302, 28492532
SCV000782316	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000918271	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 29, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10835640, 15980664, 18978175, 16849362, 23741238, 23017645 Citation Link,
SCV001174384	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 13, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10835640, 18978175, 24909264, 25927356, 27578509, 29521951, 31401021 Citation Link,
SCV001316040	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18978175, 23017645, 10835640 Citation Link,
SCV002581230	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Serine Protease Inhibitor Kazal Type 1 (SPINK1) c.194+2T > C Mutation May Predict Long-term Outcome of Endoscopic Treatments in Idiopathic Chronic Pancreatitis.

Sun C, Liu MY, Liu XG, Hu LH, Xia T, Liao Z, Li ZS.

Medicine (Baltimore). 2015 Nov;94(47):e2046. doi: 10.1097/MD.0000000000002046.

PubMed [citation]

PMID:: 26632706
PMCID:: PMC5058975

Clarifying the clinical relevance of SPINK1 intronic variants in chronic pancreatitis.

Zou WB, Boulling A, Masson E, Cooper DN, Liao Z, Li ZS, Férec C, Chen JM.

Gut. 2016 May;65(5):884-6. doi: 10.1136/gutjnl-2015-311168. Epub 2015 Dec 30. No abstract available.

PubMed [citation]

PMID:: 26719302

See all PubMed Citations (15)

Details of each submission

From GeneReviews, SCV000153735.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000253884.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects a donor splice site in intron 4 of the SPINK1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs148954387, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with chronic pancreatitis (PMID: 15980664, 23017645, 26632706). ClinVar contains an entry for this variant (Variation ID: 132142). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18978175, 26719302). For these reasons, this variant has been classified as Pathogenic.

#	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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782316.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918271.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: SPINK1 c.194+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 5/5 computational tools predict a significant impact on normal splicing. These predictions are supported by multiple functional studies, Kume_2006 and Kereszturi_2009, found the variant to significantly affect splicing. Multiple publications have cited the variant in affected individuals diagnosed with chronic pancreatitis, predominantly of Asian origin. Multiple clinical diagnostic laboratories have ClinVar submissions (after 2014) classifying the variant as "pathogenic." GeneReviews, a well-established database, classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From Ambry Genetics, SCV001174384.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

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

From Illumina Laboratory Services, Illumina, SCV001316040.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	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

From MGZ Medical Genetics Center, SCV002581230.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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