rs141576417

chr5-112780865-C-Gchr5-112780865-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000038.6(APC):c.607C>G(p.Gln203Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,612,790 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q203R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:16 O:2
• Conservation: PhyloP100: 7.29

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009639204).
• BP6: Variant 5-112780865-C-G is Benign according to our data. Variant chr5-112780865-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41509.We mark this variant Likely_benign, oryginal submissions are: {not_provided=2, Uncertain_significance=3, Likely_benign=5, Benign=7}. Variant chr5-112780865-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.607C>G	p.Gln203Glu	missense_variant	6/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.607C>G	p.Gln203Glu	missense_variant	6/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000603 AC: 151 AN: 250412 Hom.: 0 AF XY: 0.000598 AC XY: 81 AN XY: 135360

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000331 AC: 484 AN: 1460680 Hom.: 0 Cov.: 30 AF XY: 0.000352 AC XY: 256 AN XY: 726642

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000981

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74308

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000946 Hom.: 0

Bravo AF: 0.000359

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.000273

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:16 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	APC: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 19, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 28, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 19, 2015	This alteration is classified as 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. -

not specified Uncertain:1 Benign:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 2016	Variant 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 present in 1.2% of Ashkenazi Jewish alleles in gnomAD (121/10150). Frequency too high for disease. It is classified in ClinVar with 1 star as Likely benign/benign by Invitae and Ambry and as VUS by GeneDx and Biesecker lab. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2022	Variant summary: APC c.607C>G (p.Gln203Glu) results in a conservative amino acid change in 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 0.00062 in 251556 control chromosomes (gnomAD). The observed variant frequency is approximately 9 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 benign. c.607C>G has been reported in the literature in individuals affected with adrenocortical carcinoma and ependymoma (example, Zhang_2015), endometrial cancer (example, Kogan_2018), and male breast cancer (example, Rizzolo_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.68_69delAG, p.Glu23ValfsX17) providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple other ClinVar submitters (evaluation after 2014) cite the variant with a predominant consensus as as likely benign/benign (n=11) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2018	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Familial adenomatous polyposis 1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Gln203Glu variant was identified in the literature in 5 of 2506 control chromosomes (frequency: 0.002) from individuals with no personal or family history of cancer (Johnston 2012, Bodian 2014). The variant was also identified in dbSNP (ID: rs141576417) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics and GeneDx; as likely benign by Prevention Genetics, Color, and three other submitters; and as uncertain significance by one submitter), UMD (4x as "unclassified variant"), and LOVD 3.0 (1x). The variant was identified in control databases in 155 of 276178 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 129 of 10142 chromosomes (freq: 0.01), Other in 5 of 6448 chromosomes (freq: 0.0008), European in 18 of 126044 chromosomes (freq: 0.0001), and African in 3 of 24000 chromosomes (freq: 0.0001); it was not observed in the East Asian, Finnish, Latino, or South Asian populations. The p.Gln203 residue is conserved across mammals and other organisms and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

APC-Associated Polyposis Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 29, 2019

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. -

Familial multiple polyposis syndrome Benign:1

Likely benign, criteria provided, single submitter

research

University of Washington Department of Laboratory Medicine, University of Washington

May 29, 2018

The APC variant designated as NM_000038.5:c.607C>G (p.Gln203Glu) is classified as likely benign. This variant is found in approximately 1 out of 500 individuals of European ancestry (exac.broadinstitute.org), which is a higher frequency than expected of a pathogenic APC variant (Kobayashi et al, 2017, PMID:28166811). It is listed in the ClinVar database (Variation ID: 41509) and has been classified as benign or likely benign by 7 clinical laboratories. In one obseved family, this variant was identified in two members who have been documented to have fewer than 5 colon polyps on colonoscopy. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter APC function or modify cancer risk. A modest (less than 2-fold) increase in risk of cancer or colon polyps due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Desmoid disease, hereditary;C2713442:Familial adenomatous polyposis 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0096	T;T;T;T
MetaSVM	Uncertain	-0.024	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.95	.;P;P;.
Vest4		0.61, 0.65
MVP		0.88
ClinPred		0.086	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.37

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: rs141576417; hg19: chr5-112116562; COSMIC: COSV104567836; COSMIC: COSV104567836;