chr7-142751829-C-T

Variant names:

• chr7-142751829-C-T
• rs146398318
• NM_002769.5:c.256C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_002769.5(PRSS1):​c.256C>T​(p.Gln86*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000446 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: PRSS1 NM_002769.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.83

Genes affected

PRSS1 (HGNC:9475): (serine protease 1) This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is secreted by the pancreas and cleaved to its active form in the small intestine. It is active on peptide linkages involving the carboxyl group of lysine or arginine. Mutations in this gene are associated with hereditary pancreatitis. This gene and several other trypsinogen genes are localized to the T cell receptor beta locus on chromosome 7. [provided by RefSeq, Jul 2008]

TRB (HGNC:12155):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.256C>T	p.Gln86*	stop_gained	Exon 3 of 5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.256C>T	p.Gln86*	stop_gained	Exon 3 of 5	1	NM_002769.5	ENSP00000308720.7

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251488 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461892 Hom.: 0 Cov.: 82 AF XY: 0.0000523 AC XY: 38 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74286

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000571 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:3

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q86* variant (also known as c.256C>T), located in coding exon 3 of the PRSS1 gene, results from a C to T substitution at nucleotide position 256. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This variant has been observed in a study of patients with Hereditary Diffuse Gastric Cancer; this patient had diffuse gastric cancer at age 42 and a family history of gastric cancer (Hansford S et al. JAMA Oncol, 2015 Apr;1:23-32). This alteration was also identified in a cohort of patients with pancreatic cancer or other periampullary neoplasms tested for hereditary cancer risk via a multi-gene panel (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390). In addition to the clinical data presented in the literature, this alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of PRSS1 has not been clearly established as a mechanism of disease. Based on the available evidence, the clinical significance of this variant remains unclear. -

May 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRSS1 c.256C>T; p.Gln86Ter variant (rs146398318; ClinVar Variation ID: 576677) is reported in the literature in one individual with hereditary diffuse gastric cancer and was identified in a cohort of individuals recruited for cardiovascular disease trait (Hansford 2015 and Glicksberg 2019); though none of these individuals were reported to be affected with pancreatitis. This variant is found in the non-Finnish European population with an allele frequency of 0.01% (13/129182 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon in exon 3 of 5 and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. However, the loss of PRSS1 activity has been suggested to be protective against pancreatitis, and is supported by the absence of any nonsense or canonical splice site variants associated with hereditary pancreatitis (Chen 2003). Although the p.Gln86Ter variant is considered unlikely to be disease-causing for pancreatitis, it is unknown if the variant could be associated with other clinical symptoms. References: Chen J et al. "Loss of function" mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis. Mol Genet Metab. 2003; 79(1):67-70. Glicksberg BS et al. Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. BMC Med Genomics. 2019 Jul 25;12(Suppl 6):108. PMID: 31345219 Hansford S et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015 Apr;1(1):23-32. PMID: 26182300. -

Jun 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln86*) in the PRSS1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PRSS1 cause disease. 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 diffuse gastric cancer (PMID: 26182300). ClinVar contains an entry for this variant (Variation ID: 576677). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.90
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146398318; hg19: chr7-142459680;