rs148275069

chr5-112840734-G-Achr5-112840734-G-Cchr5-112840734-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000038.6(APC):c.5140G>A(p.Asp1714Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000267 in 1,614,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1714G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:8
• Conservation: PhyloP100: 4.03

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16178542).
• BP6: Variant 5-112840734-G-A is Benign according to our data. Variant chr5-112840734-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135706.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=7}. Variant chr5-112840734-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.5140G>A	p.Asp1714Asn	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.5140G>A	p.Asp1714Asn	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 46 AN: 250168 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135330

Gnomad AFR exome AF: 0.000187

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: 0.0000924

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461808 Hom.: 1 Cov.: 64 AF XY: 0.000286 AC XY: 208 AN XY: 727214

Gnomad4 AFR exome AF: 0.000119

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: 0.0000375

Gnomad4 NFE exome AF: 0.000341

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 06, 2023	Variant summary: APC c.5140G>A (p.Asp1714Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250168 control chromosomes, predominantly at a frequency of 0.00035 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 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5140G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Azzopardi_2008, Out_2015, Rohlin_2017) but has also been reported in patients with other phenotypes, including breast cancer and medulloblastoma (e.g. Tung_2015, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Experimental evidence evaluating an impact on protein function, demonstrated the variant alters beta-catenin-regulated transcription (CRT) in vitro (e.g. Azzopardi_2008). However, no definitive conclusions can be drawn about the clinical relevance of this finding. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2019	- -

Familial adenomatous polyposis 1 Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 02, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Asp1714Asn variant was identified in 2 of 1564 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer or adenomatous polyposis and was present in 1 of 1938 control chromosomes (frequency: 0.001) from healthy individuals (Azzopardi 2008, Rohlin 2017). The variant was also identified in dbSNP (ID: rs148275069) as "With Uncertain significance, other allele”, ClinVar (classified as likely benign by GeneDx, Ambry Genetics and Integrated Genetics/Laboratory Corporation of America; and as uncertain significance by five submitters), and in LOVD 3.0. The variant was identified in control databases in 46 of 276088 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23960 chromosomes (freq: 0.00008), Other in 2 of 6444 chromosomes (freq: 0.0003), European in 40 of 125810 chromosomes (freq: 0.0003), and Finnish in 2 of 25786 chromosomes (freq: 0.00008), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Asp1714 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Asn variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 26, 2018	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. -

APC-Associated Polyposis Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

APC-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

The APC c.5140G>A variant is predicted to result in the amino acid substitution p.Asp1714Asn. This variant has been reported in individuals with polyposis colorectal adenomas (Azzopardi et al. 2008. PubMed ID: 18199528; Rey et al. 2017. PubMed ID: 28502729; Rohlin et al. 2017. PubMed ID: 27696107; Patel et al. 2021. PubMed ID: 33436027), breast cancer (Supporting Information 2 - Tung et al. 2014. PubMed ID: 25186627), ovarian cancer (Schwarz et al. 2015. PubMed ID: 25710373), or medulloblastoma (Table S4a - Zhang et al. 2015. PubMed ID: 26580448). It was also reported as a variant of uncertain significance in a study of incidental findings on exome testing (Amendola et al. 2015. PubMed ID: 25637381; Olfson et al. 2015. PubMed ID: 26332594). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112176431-G-A). In ClinVar, it has conflicting interpretations of pathogenicity, ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/135706/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.35	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.36	B;B
Vest4		0.67
MVP		0.83
ClinPred		0.049	T
GERP RS		6.2
Varity_R		0.16
gMVP		0.33

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

Other links and lift over

dbSNP: rs148275069; hg19: chr5-112176431; COSMIC: COSV57358636; COSMIC: COSV57358636;