5-112840512-C-T

Variant summary

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

The NM_000038.6(APC):c.4918C>T(p.Arg1640Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,986 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. R1640Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:2
• Conservation: PhyloP100: 0.826

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, 0.792
• BP6: Variant 5-112840512-C-T is Benign according to our data. Variant chr5-112840512-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142246.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Benign=1, Likely_benign=1}. Variant chr5-112840512-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4918C>T	p.Arg1640Trp	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4918C>T	p.Arg1640Trp	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251166 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135722

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000794 AC: 116 AN: 1461868 Hom.: 0 Cov.: 66 AF XY: 0.0000770 AC XY: 56 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000706 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 12, 2021	The APC c.4918C>T (p.Arg1640Trp) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112176209-C-T?dataset=gnomad_r2_1). This variant has been reported in individuals with familial adenomatous polyposis (PMID: 7833931, 20233475) and has been found to segregate with disease in affected family members (PMID: 20233475). It has also been reported in an individual with a personal and/or family history suggestive of Li-Fraumeni syndrome who did not harbor pathogenic germline variants in BRCA1/2, or TP53 (PMID: 30086788). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria met. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1640 of the APC protein (p.Arg1640Trp). This variant is present in population databases (rs373440614, gnomAD 0.01%). This missense change has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 7833931, 20233475). It has also been observed to segregate with disease in related individuals. This variant is also known as 4921C>T, Arg1841Trp. ClinVar contains an entry for this variant (Variation ID: 142246). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, thrombocytopenia, and features of Familial Adenomatous Polyposis (Scott et al., 2004; Penkert et al., 2018; Kewan et al., 2020); This variant is associated with the following publications: (PMID: 25637381, 21859464, 24055113, 20233475, 7833931, 27150160, 30086788, 32618208, 34426522, 18199528) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Arg1640Trp variant was identified in 1 of 224 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis (Scott 2004). The variant was also identified in dbSNP (ID: rs373440614) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Color, Ambry Genetics and two clinical laboratories), Cosmic (1x in Stomach tissue), and in LOVD 3.0 (1x). The variant was not identified in COGR, MutDB, UMD-LSDB, or the Zhejiang University database. The variant was identified in 20 of 276908 chromosomes at a frequency of 0.00007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6458 chromosomes (freq: 0.0002), European in 18 of 126442 chromosomes (freq: 0.0001), East Asian in 1 of 18864 chromosomes (freq: 0.00005); it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Arg1640 residue is conserved across mammals and other organisms, and 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. This variant is classified as a variant of uncertain significance. -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2019	Variant summary: APC c.4918C>T (p.Arg1640Trp) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein repeat (IPR009223) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251366 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European 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), suggesting that the variant is in the benign spectrum. c.4918C>T has been reported in the literature in individuals affected with Li-Fraumeni(-like) breast cancer and Familial Adenomatous Polyposis (Penkert_2018, Scott_2004). Additionally, the variant was shown to segregate with disease (FAP) in a small family study (Stella_1994). However the possibility of co-incidental co-segregation cannot be ruled out. The testing was a PCR-based SSCP screening approach. These data indicate that the variant may be associated with disease. Co-occurrence with a likely pathogenic variant has been reported (ATM c.2192dupA, p.Tyr731X; Internal sample). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2018	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2023	This missense variant replaces arginine with tryptophan at codon 1640 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 11317365, 20233475, 7833931, 8888441), an individual affected with breast cancer (PMID: 29684080), an individual affected with a serous gynecological cancer (PMID: 27150160). This variant has also been identified in 22/282560 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 18, 2021	This alteration is classified as 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. -

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

Feb 05, 2024

This missense variant replaces arginine with tryptophan at codon 1640 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 11317365, 20233475, 7833931, 8888441), an individual affected with breast cancer (PMID: 29684080), an individual affected with a serous gynecological cancer (PMID: 27150160). This variant has also been identified in 22/282560 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.43	N
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.037	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.17	T;T
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.83
MVP		0.91
ClinPred		0.16	T
GERP RS		4.3
Varity_R		0.087
gMVP		0.62

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: rs373440614; hg19: chr5-112176209; COSMIC: COSV57339367; COSMIC: COSV57339367;