NM_000038.6:c.835-3T>C

Variant names:

• chr5-112815492-T-C
• rs372090940
• NM_000038.6:c.835-3T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000038.6(APC):​c.835-3T>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 0.0000423 in 1,608,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.0006409
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 2.55
• Publications: 0 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 5-112815492-T-C is Benign according to our data. Variant chr5-112815492-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 185141.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.835-3T>C		splice_region_variant, intron_variant	Intron 8 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.835-3T>C		splice_region_variant, intron_variant	Intron 8 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250968 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000446 AC: 65 AN: 1456716 Hom.: 0 Cov.: 30 AF XY: 0.0000345 AC XY: 25 AN XY: 725014

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000587 AC: 65 AN: 1108212

Other (OTH) AF: 0.00 AC: 0 AN: 60078

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000340 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Nov 19, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the APC gene demonstrated a sequence change in intron 8, c.835-3T>C. This sequence change has been described in the gnomAD database with a frequency of 0.004% in the non-Finnish European subpopulation (dbSNP rs372090940). This sequence change is not predicted to have a deleterious effect on splicing based on in-silico splice prediction programs. This sequence change has been previously described in an individual with colorectal cancer (PMID: 28135145). It is possible that this sequence change represents a benign sequence change in the APC gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined. -

Jul 04, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.835-3T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250968 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.835-3T>C has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with colorectal cancer (example, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with a majority consensus leaning towards benign (n=1)/likely benign(n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 01, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial adenomatous polyposis 1 Uncertain:1 Benign:2

Feb 16, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Benign:2

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Jun 19, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 11, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00064
dbscSNV1_RF	Benign	0.012
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs372090940; hg19: chr5-112151189;