rs147863331

chr5-112835032-G-Achr5-112835032-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000038.6(APC):c.1825G>A(p.Val609Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,140 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. V609A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 9.60

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 -11 ACMG points.

• PM1: In a repeat ARM 4 (size 46) in uniprot entity APC_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_000038.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.015657783).
• BP6: Variant 5-112835032-G-A is Benign according to our data. Variant chr5-112835032-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00088 (134/152316) while in subpopulation AFR AF= 0.00313 (130/41574). AF 95% confidence interval is 0.00269. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1825G>A	p.Val609Ile	missense_variant	15/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1825G>A	p.Val609Ile	missense_variant	15/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000880 AC: 134 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251294 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135806

Gnomad AFR exome AF: 0.00394

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727216

Gnomad4 AFR exome AF: 0.00338

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74490

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000202 Hom.: 0

Bravo AF: 0.00103

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000362 AC: 44

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	APC: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	This variant is associated with the following publications: (PMID: 23159591, 25980754, 22585170, 26802149, 27978560, 28135145, 28873162, 26667234) -

Familial adenomatous polyposis 1 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 22, 2023	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 07, 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 03, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 19, 2018

Variant summary: APC c.1825G>A (p.Val609Ile) results in a conservative amino acid change located in the Armadillo 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 0.0003 in 277028 control chromosomes. The observed variant frequency is approximately 4.19 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.1825G>A has been reported in the literature in individuals affected with colorectal cancer, Lynch syndrome, breast cancer, and other unspecified phenotypes (Kerr_2013, Liang_2016, Pearlman_2016, Yurgelun_2017, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrences with other pathogenic variant(s) have been reported (TP53 c.742C>T, p.Arg248Trp; APC c.3927_3931delAAAGA, p.Glu1309fsX4, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign. -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Val609Ile variant was identified in 5 of 8718 proband chromosomes (frequency: 0.0006) from individuals or families with colorectal cancer (Kerr 2012, Pearlman 2017, Yurgelun 2015, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs147863331) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and three other submitters; as uncertain significance by Counsyl), and in LOVD 3.0 (1x as VUS). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 83 of 277028 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 83 of 24034 chromosomes (freq: 0.003), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was identified in our laboratory with a co-occurring pathogenic APC variant (c.4391_4394del, p.Glu1464Valfs*8), increasing the likelihood that the p.Val609Ile variant does not have clinical significance. The p.Val609 residue is conserved across mammals and other organisms, and four out of five 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Uncertain	-0.0079	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.90	N;N;N;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.034	D;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.99	.;D;D;.;.
Vest4		0.67, 0.55
MVP		0.78
ClinPred		0.16	T
GERP RS		5.9
Varity_R		0.61
gMVP		0.53

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: rs147863331; hg19: chr5-112170729; COSMIC: COSV57347683;