rs377278397

chr5-112838968-T-Cchr5-112838968-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000038.6(APC):c.3374T>C(p.Val1125Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,613,984 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. V1125I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 4.74

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00506413).
• BP6: Variant 5-112838968-T-C is Benign according to our data. Variant chr5-112838968-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132749.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=9, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000177 (27/152132) while in subpopulation EAS AF= 0.00501 (26/5188). AF 95% confidence interval is 0.00351. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.3374T>C	p.Val1125Ala	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.3374T>C	p.Val1125Ala	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000607 AC: 152 AN: 250618 Hom.: 1 AF XY: 0.000679 AC XY: 92 AN XY: 135506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00806

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 98 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00363

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000796 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2021	Variant summary: APC c.3374T>C (p.Val1125Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251058 control chromosomes, predominantly at a frequency of 0.0081 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 113 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 East Asian origin. c.3374T>C, has been reported in the literature in individuals affected with Familial Adenomatous Polyposis and other gastrointestinal polyposes/cancers, however without strong evidence for pathogenicity (example, Chang_2016, Kohda_2016, Li_2015, Grant_2015, Azzopard_2008, Tung_2016). In a Chinese family, this variant seemed to segregate with the disease in five affected members with FAP syndrome, however it cannot be ruled out that other undetected pathogenic variants could have actually explained the phenotype (Li_2015). Therefore 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. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=9; VUS, n=1). Based on the evidence outlined above reflecting the consensus among peers the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial adenomatous polyposis 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 12, 2018	- -
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. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 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	Aug 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 26, 2016	- -

Neoplasm of the liver Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Jan 12, 2017

- -

APC-Associated Polyposis Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 03, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely 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.Val1125Ala variant was identified in 5 of 2666 proband chromosomes (frequency: 0.002) from individuals or families with colon and breast cancer (Chen 2006, Azzopardi 2008, Tung 2016). The variant was also identified in dbSNP (ID: rs377278397) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, likely benign by Ambry Genetics and Illumina, and benign by Invitae), Clinvitae (4x), and Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, MutDB, LOVD 3.0, and UMD-LSDB databases. The variant was identified in control databases in 167 of 276336 chromosomes at a frequency of 0.0006 in the following populations: African in 1 of 23940 chromosomes (freq. 0.00004), East Asian in 160 (1 homozygous) of 18838 chromosomes (freq. 0.008), Other in 4 of 6452 chromosomes (freq. 0.0006), South Asian in 1 of 30754 chromosomes (freq. 0.00003), and Latino in 1 of 34390 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val1125Ala residue is conserved in in mammals but not in more distantly related organisms, with the variant amino acid Alanine (Ala) present in the African clawed frog, however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.33
Cadd	Benign	20
Dann	Benign	0.95
Eigen	Benign	-0.18
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0051	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.34	N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.83	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.87, 0.73
MutPred		0.64		.;Loss of stability (P = 0.0328);Loss of stability (P = 0.0328);Loss of stability (P = 0.0328);
MVP		1.0
ClinPred		0.024	T
GERP RS		5.8
Varity_R		0.031
gMVP		0.47

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: rs377278397; hg19: chr5-112174665; COSMIC: COSV57340743; COSMIC: COSV57340743;