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rs2229993

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000038.6(APC):c.6921G>A(p.Ser2307=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,912 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2307S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: -0.254
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 5-112842515-G-A is Benign according to our data. Variant chr5-112842515-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112842515-G-A is described in Lovd as [Likely_benign]. Variant chr5-112842515-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.254 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00135 (206/152162) while in subpopulation NFE AF= 0.00235 (160/67990). AF 95% confidence interval is 0.00206. There are 1 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High AC in GnomAd at 207 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APCNM_000038.6 linkuse as main transcriptc.6921G>A p.Ser2307= synonymous_variant 16/16 ENST00000257430.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.6921G>A p.Ser2307= synonymous_variant 16/165 NM_000038.6 P1P25054-1

Frequencies

GnomAD3 genomes
AF:
0.00136
AC:
207
AN:
152044
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000628
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.000849
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00235
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00145
AC:
364
AN:
250966
Hom.:
1
AF XY:
0.00143
AC XY:
194
AN XY:
135640
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.000666
Gnomad ASJ exome
AF:
0.000199
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00102
Gnomad NFE exome
AF:
0.00263
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.00220
AC:
3211
AN:
1461750
Hom.:
5
Cov.:
34
AF XY:
0.00213
AC XY:
1550
AN XY:
727178
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.000268
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00152
Gnomad4 NFE exome
AF:
0.00264
Gnomad4 OTH exome
AF:
0.00224
GnomAD4 genome
AF:
0.00135
AC:
206
AN:
152162
Hom.:
1
Cov.:
32
AF XY:
0.00116
AC XY:
86
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.000626
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000849
Gnomad4 NFE
AF:
0.00235
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00182
Hom.:
0
Bravo
AF:
0.00155
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00273
EpiControl
AF:
0.00202

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:9
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo Clinic-- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 06, 2014This 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. -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 30, 2019- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 27, 2017- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 03, 2017- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
not provided Benign:6
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024APC: BP4, BP7, BS1 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 23, 2016Variant summary: The APC c.6921G>A variant affects a non-conserved nucleotide, resulting in a synonymous change at Ser2307. 5/5 Alamut algorithms predict no significant change to normal splicing. ESEfinder predicts a loss of binding motif for RNA splicing enhancer. These in silico predictions have not been verified with in vitro/in vivo functional studies. This variant was found in 169/120898 control chromosomes at a frequency of 0.0013979, which is about 23 times the maximal expected frequency of a pathogenic APC allele (0.0000602), suggesting this variant is benign. In addition, multiple clinical laboratories database classified this variant as benign. Taken together, this variant was classified as benign. -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Hereditary cancer-predisposing syndrome Benign:5
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 18, 2016- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 13, 2014This alteration is classified as benign based on a combination of the following: 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. -
Benign, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Apr 18, 2023- -
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsSep 11, 2017- -
Benign, criteria provided, single submittercurationSema4, Sema4Oct 18, 2020- -
Carcinoma of colon Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The APC, c.6921G>A, p.Ser2307Ser variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It is listed in dbSNP database (ID#: rs2229993) with a global minor allele frequency (MAF) of 0.001/3. It has been reported in the InSiGHT colon cancer database as a rare familial variant found in a proband with an attenuated colorectal phenotype and sebaceous cysts. The number of probands with the variant, was not provided. In addition, this variant is not of the type that is expected to cause the disorder. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in this individual, but based on the above information this variant is classified as predicted benign. -
APC-Associated Polyposis Disorders Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -
Familial adenomatous polyposis 1 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
Cadd
Benign
1.6
Dann
Benign
0.76

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: rs2229993; hg19: chr5-112178212; COSMIC: COSV104567403; COSMIC: COSV104567403; API