chr5-112835173-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000038.6(APC):​c.1958+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,602,474 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 19 hom., cov: 32)
Exomes 𝑓: 0.0034 ( 109 hom. )

Consequence

APC
NM_000038.6 splice_region, intron

Scores

2
Splicing: ADA: 0.0002136
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: -0.407
Variant links:
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 5-112835173-T-C is Benign according to our data. Variant chr5-112835173-T-C is described in ClinVar as [Benign]. Clinvar id is 82616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112835173-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0743 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APCNM_000038.6 linkc.1958+8T>C splice_region_variant, intron_variant Intron 15 of 15 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkc.1958+8T>C splice_region_variant, intron_variant Intron 15 of 15 5 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkn.228+6201T>C intron_variant Intron 3 of 7 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
AF:
0.00578
AC:
880
AN:
152190
Hom.:
19
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00577
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.0803
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.000471
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00229
Gnomad OTH
AF:
0.00624
GnomAD3 exomes
AF:
0.00797
AC:
1911
AN:
239770
Hom.:
68
AF XY:
0.00748
AC XY:
971
AN XY:
129772
show subpopulations
Gnomad AFR exome
AF:
0.00647
Gnomad AMR exome
AF:
0.00106
Gnomad ASJ exome
AF:
0.00222
Gnomad EAS exome
AF:
0.0841
Gnomad SAS exome
AF:
0.00149
Gnomad FIN exome
AF:
0.000471
Gnomad NFE exome
AF:
0.00194
Gnomad OTH exome
AF:
0.00506
GnomAD4 exome
AF:
0.00343
AC:
4972
AN:
1450166
Hom.:
109
Cov.:
28
AF XY:
0.00346
AC XY:
2500
AN XY:
721684
show subpopulations
Gnomad4 AFR exome
AF:
0.00551
Gnomad4 AMR exome
AF:
0.00108
Gnomad4 ASJ exome
AF:
0.00257
Gnomad4 EAS exome
AF:
0.0641
Gnomad4 SAS exome
AF:
0.00155
Gnomad4 FIN exome
AF:
0.000752
Gnomad4 NFE exome
AF:
0.00152
Gnomad4 OTH exome
AF:
0.00469
GnomAD4 genome
AF:
0.00582
AC:
886
AN:
152308
Hom.:
19
Cov.:
32
AF XY:
0.00602
AC XY:
448
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00592
Gnomad4 AMR
AF:
0.00183
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.0807
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.000471
Gnomad4 NFE
AF:
0.00229
Gnomad4 OTH
AF:
0.00570
Alfa
AF:
0.00311
Hom.:
0
Bravo
AF:
0.00631
Asia WGS
AF:
0.0230
AC:
79
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:18Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 26, 2012
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Benign:3
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 07, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3
Sep 29, 2017
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 22, 2022
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 21, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 23, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

APC-Associated Polyposis Disorders Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Carcinoma of colon Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The c.1958+8T>C variant has been reported once in the InSiGHT database in an individual with familial adenomatous polyposis. It is listed in the dbSNP database (rs#:62626346) and reported from the 1000 genomes project (frequency: 0.026) and in a Chinese and Japanese cohort (frequency: 0.067) as well as the exome variant server as a low frequency variant increasing the likelihood this variant does not have clinical significance. The variant is located in the 5' splice region but does not affect the highly conserved +1 and +2 positions. In summary, based on above information this variant meets our laboratory's criteria to be classified benign. -

Familial colorectal cancer Other:1
-
Systems Biology Platform Zhejiang California International NanoSystems Institute
Significance: other
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
5.6
DANN
Benign
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00021
dbscSNV1_RF
Benign
0.13
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62626346; hg19: chr5-112170870; COSMIC: COSV57373884; API