5-112843009-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.7415C>T(p.Ala2472Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. A2472G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 2.83

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=0.040541023).
• BP6: Variant 5-112843009-C-T is Benign according to our data. Variant chr5-112843009-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41513.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=4}.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.7415C>T	p.Ala2472Val	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.7415C>T	p.Ala2472Val	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251162 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461712 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74488

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2023	In the published literature, this variant has been reported in individuals and families affected with breast cancer (PMIDs: 27153395 (2016), 25186627 (2015)), colorectal cancer (PMID: 28135145 (2017)), and unaffected individuals (PMIDs: 24123366 (2014), 22703879 (2012)). The frequency of this variant in the general population, 0.00011 (4/35406 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools or the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	This variant is denoted APC c.7415C>T at the cDNA level, p.Ala2472Val (A2472V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). APC Ala2472Val has been reported in a patient with colorectal cancer (Yurgelun 2017), in two patients with breast and/or ovarian cancer (Maxwell 2016), and in two individuals with no specific information provided regarding cancer history (Johnston 2012, Rodriguez-Flores 2014). APC Ala2472Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Ala2472Val is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ala2472Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 29, 2018	The APC c.7415C>T; p.Ala2472Val variant (rs200399245) is reported in the medical literature in two individuals with breast cancer (Maxwell 2016) and in one individual with colorectal cancer (Yurgelun 2016). However, the variant is also described in individuals not selected for a personal or family history of cancer (Johnston 2012, Rodriguez-Flores 2014). The variant is reported in the ClinVar database (Variation ID: 41513). The variant is also listed in the Genome Aggregation Database in 9/276906 alleles. The alanine at this position is weakly conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. However, the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Pathogenic APC variants are causative for adenomatous polyposis coli (MIM: 175100). References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/ Johnston JJ et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Maxwell KN et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016 May 5;98(5):801-817. Rodriguez-Flores JL et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat. 2014 Jan;35(1):105-16. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. -

Familial adenomatous polyposis 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 23, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 20, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2023	This missense variant replaces alanine with valine at codon 2472 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145) and breast/ovarian cancer (PMID: 25186627 , 27153395; DOI: 10.1101/2021.04.15.21255554v2) in the literature, but has also been observed in populations not selected for cancer (PMID: 22703879, 24123366). The variant has also been observed to co-occur with an APC truncation in the NA11410 colorectal cancer cell line. This variant has been identified in 11/282564 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2021	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 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2024	Variant summary: APC c.7415C>T (p.Ala2472Val) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251162 control chromosomes, predominantly at a frequency of 0.00012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2-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 Latino origin. c.7415C>T has been reported in the literature in an individual affected with colorectal cancer (Yurgelun_2017) and individuals with breast cancer (Tung_2015, de Oliveira_2022) without strong evidence for causality.These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 27153395, 27600092, 24123366, 25186627, 28135145, 35534704). ClinVar contains an entry for this variant (Variation ID: 41513). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 16, 2016	- -

APC-Associated Polyposis Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	12
Dann	Benign	0.92
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.17
Sift	Benign	0.072	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0030	B;B
Vest4		0.052
MutPred		0.57		Loss of glycosylation at P2471 (P = 0.0795);Loss of glycosylation at P2471 (P = 0.0795);
MVP		0.83
ClinPred		0.032	T
GERP RS		2.3
Varity_R		0.036
gMVP		0.44

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: rs200399245; hg19: chr5-112178706;