rs201004111

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000038.6(APC):​c.3479C>A​(p.Thr1160Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00027 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

1
9
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:6

Conservation

PhyloP100: 4.82
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35579753).
BP6
Variant 5-112839073-C-A is Benign according to our data. Variant chr5-112839073-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41503.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=5, Benign=1}.
BS2
High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APCNM_000038.6 linkc.3479C>A p.Thr1160Lys missense_variant 16/16 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkc.3479C>A p.Thr1160Lys missense_variant 16/165 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkn.228+10101C>A intron_variant 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000957
AC:
24
AN:
250788
Hom.:
0
AF XY:
0.0000811
AC XY:
11
AN XY:
135644
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000212
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000282
AC:
412
AN:
1461774
Hom.:
0
Cov.:
33
AF XY:
0.000278
AC XY:
202
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000344
Gnomad4 OTH exome
AF:
0.000497
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000237
Hom.:
0
Bravo
AF:
0.000136
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.000327
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 21, 2023BS1 -
Uncertain significance, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 14, 2022In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of colorectal adenomas or colorectal cancer (Azzopardi et al., 2008; Raskin et al., 2017); This variant is associated with the following publications: (PMID: 33918692, Biswas2021[abstract], 22703879, 25637381, 21859464, 18199528, 27150160, 27600092, 29212164, 28873162, 30709382, 35128723, 26580448, 35145771) -
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoAug 03, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 16, 2022- -
Familial adenomatous polyposis 1 Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylNov 24, 2015- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 23, 2023This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 29, 2018This 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. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jan 27, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 19, 2023This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 24, 2017Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DM in HGMD - it has been seen in one patient with colorectal adenoma and one unaffected patient. It has been classified with 1 star as VUS by 4 sumitters (GeneDx, Invitae, CSER_CC_NCGL, Biesecker lab) and Likely benign by 1 (Ambry). MaxMAF is 0.02% in ExAC (high for disease prevalence). -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 24, 2024Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in the one of the 15 residue repeat domains (IPR009240) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 1613950 control chromosomes, predominantly at a frequency of 0.00048 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). c.3479C>A has been reported in the literature in individuals affected with non-FAP non-MAP colorectal adenomas (example, Azzopardi 2008), in a family with colorectal cancer without polyps (example, Raskin 2017) and as a VUS in settings of multigene panel testing performed in an individual with Serrated Polyposis Syndrome (SPS) (example, Murphy_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 18199528, 26580448, 29212164, 35128723). ClinVar contains an entry for this variant (Variation ID: 41503). Based on the evidence outlined above, the variant was classified as likely benign. -
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 23, 2024This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
APC-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 30, 2024The APC c.3479C>A variant is predicted to result in the amino acid substitution p.Thr1160Lys. This variant was reported in multiple individuals with colorectal adenoma, but was also present in one unaffected 48 year old family member (Azzopardi et al. 2008. PubMed ID: 18199528; Table S1, Minde et al. 2011. PubMed ID: 21859464; Raskin et al. 2017. PubMed ID: 29212164). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112174770-C-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/41503/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Colorectal adenoma Uncertain:1
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Uncertain
0.51
D;D;T
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
.;D;D
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.36
T;T;T
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
0.90
L;L;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.60
N;N;N
REVEL
Uncertain
0.52
Sift
Benign
0.034
D;D;D
Sift4G
Benign
0.51
T;T;T
Polyphen
0.61
P;P;.
Vest4
0.95
MVP
0.99
ClinPred
0.15
T
GERP RS
5.8
Varity_R
0.13
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs201004111; hg19: chr5-112174770; COSMIC: COSV57403576; COSMIC: COSV57403576; API