NM_000038.6:c.1825G>A

Variant names:

• chr5-112835032-G-A
• rs147863331
• NM_000038.6:c.1825G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

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 Likely benign (★★). 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: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 9.60
• Publications: 11 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 127278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1825G>A	p.Val609Ile	missense_variant	Exon 15 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1825G>A	p.Val609Ile	missense_variant	Exon 15 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+6060G>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

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

GnomAD2 exomes AF: 0.000259 AC: 65 AN: 251294 AF XY: 0.000162

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 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

African (AFR) AF: 0.00338 AC: 113 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111974

Other (OTH) AF: 0.0000994 AC: 6 AN: 60392

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

African (AFR) AF: 0.00313 AC: 130 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000264 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: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Aug 30, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23159591, 25980754, 22585170, 26802149, 27978560, 28135145, 28873162, 26667234) -

Jun 21, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: BS1 -

Familial adenomatous polyposis 1 Uncertain:1 Benign:2

Dec 18, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 22, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Nov 03, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 22, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Nov 19, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
DEOGEN2	Uncertain	0.65	.;D;D;T;T
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
MutationAssessor	Uncertain	2.7	.;M;M;.;.
PhyloP100		9.6
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
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

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