rs202199891

chr5-112827969-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_000038.6(APC):c.1589T>C(p.Val530Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V530L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 7.67

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 Likely_benign. Variant got -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• BP6: Variant 5-112827969-T-C is Benign according to our data. Variant chr5-112827969-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219535.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1589T>C	p.Val530Ala	missense_variant	13/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1589T>C	p.Val530Ala	missense_variant	13/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250846 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000801 AC: 117 AN: 1460934 Hom.: 0 Cov.: 30 AF XY: 0.0000674 AC XY: 49 AN XY: 726792

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74522

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 21, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2023	This missense variant replaces valine with alanine at codon 530 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with colorectal adenomas (PMID: 22773231, Cetani 2017), familial adenomatous polyposis (PMID: 23159591), attenuated adenomatous polyposis (PMID: 22976915), colorectal cancer (PMID: 28135145). This variant has been identified in 8/250846 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Familial adenomatous polyposis 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2018	Variant summary: APC c.1589T>C (p.Val530Ala) affects a conserved nucleotide and results in a non-conservative amino acid change located in an Armadillo repeat domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245588 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1589T>C has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (FAP) (Kerr 2013), attenuated FAP (AFAP) (deLeon 2013, Urso 2012) and Colorectal Cancer (Yurgelun 2017). These reports 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2016	The p.Val530Ala variant in APC has been reported in three individuals: 1 with a ttenuated familial adenomatous polyposis (AFAP; de Leon 2013), 1 with multiple colorectal adenomas (Urso 2013), and 1 with suspected FAP (Kerr 2013). This vari ant has also been identified in 3/66436 of European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202199891). C omputational prediction tools and conservation analysis suggest that the p.Val53 0Ala variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, the clinical significance of the p .Val530Ala variant is uncertain. -

Classic or attenuated familial adenomatous polyposis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

This missense variant replaces valine with alanine at codon 530 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 observed in individuals affected with colorectal adenomas (PMID: 22773231, Cetani 2017), familial adenomatous polyposis (PMID: 23159591), attenuated adenomatous polyposis (PMID: 22976915) or colorectal cancer (PMID: 28135145). This variant has been identified in 8/250846 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least two individuals with multiple colorectal adenomas or polyposis, an individual being evaluated for Familial Adenomatous Polyposis (FAP), and an individual with colorectal cancer (de Leon et al., 2013; Kerr et al., 2013; Urso et al., 2013; Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 22976915, 23159591, 22773231, 28135145, 31159747, 31486992, 18199528) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	D;D;D;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.93, 0.92
MVP		0.85
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.69
gMVP		0.69

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: rs202199891; hg19: chr5-112163666;