5-112843215-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000038.6(APC):c.7621A>G(p.Ile2541Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. I2541T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4 O:1
• Conservation: PhyloP100: 1.45

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=0.066997826).
• BP6: Variant 5-112843215-A-G is Benign according to our data. Variant chr5-112843215-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133514.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, not_provided=1, Likely_benign=3, Uncertain_significance=5}. Variant chr5-112843215-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.7621A>G	p.Ile2541Val	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.7621A>G	p.Ile2541Val	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 250678 Hom.: 0 AF XY: 0.0000960 AC XY: 13 AN XY: 135430

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461532 Hom.: 0 Cov.: 34 AF XY: 0.0000811 AC XY: 59 AN XY: 727076

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74356

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000918 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with multiple colorectal adenomas (Azzopardi et al., 2008); This variant is associated with the following publications: (PMID: 26373574, 21859464, 24728327, 24599579, 30836094, 34378333, 18199528) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Ile2541Val variant was identified in 1 of 1382 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal adenomas and was present in 1 of 3300 control chromosomes (frequency: 0.0003) from healthy individuals (Azzopardi 2008, Bodian 2014). The variant was also identified in dbSNP (ID: rs587778033) as "With Uncertain significance allele", ClinVar (classified as likely benign by Color and Ambry Genetics; as uncertain significance by Invitae, GeneDx and three other submitters), and UMD-LSDB (2x as neutral). The variant was not identified in LOVD 3.0 . The variant was identified in control databases in 26 of 276400 chromosomes at a frequency of 0.00009 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: African in 3 of 24028 chromosomes (freq: 0.0001), Other in 1 of 6448 chromosomes (freq: 0.0002), Latino in 2 of 34396 chromosomes (freq: 0.00006), European in 13 of 125980 chromosomes (freq: 0.0001), Ashkenazi Jewish in 1 of 10126 chromosomes (freq: 0.0001), and South Asian in 6 of 30780 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian, and European , populations. The p.Ile2541 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2016	Variant summary: The APC c.7621A>G (p.Ile2541Val) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 7/123492 (1/17636; frequency of 0.0000567), predominantly observed in the European (Non-Finnish) cohort, 5/66712 (1/13342), which does exceed the estimated maximal expected allele frequency for a pathogenic APC variant of 1/17636 (0.0000714). Therefore, suggesting that the varinat is a rare polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has been reported in affected individuals, although with limited information (ie lack of co-occurrence and cosegregation data), along with an internal LCA sample reporting the variant to co-occur with a deleterious BRCA2 variant, c.9117G>A (classified as pathogenic by LCA). In addition, multiple reputable databases/clinical laboratories have cited the variant with conflicting classifications "Neutral" or "Uncertain Signicance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "VUS-possible benign," until addtional information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2021	The p.Ile2541Val variant in APC has been reported in 1 individual with multiple colorectal adenomas (Azzopardi 2008 PMID: 18199528), but has also been identified in a healthy adult (Bodian 2014 PMID: 24728327) and in 0.02% (6/30614) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Isoleucine (Ile) at position 2541 is not well conserved: Four mammals (Chinese tree shrew, rabbit, pika, and star-nosed mole) carry a valine (Val) at this position despite high nearby amino acid conservation, suggesting that this change may be tolerated. Finally, this variant has been reported in ClinVar with conflicting interpretations (Likely Benign and Variant of Uncertain Significance; Variation ID# 133514). In summary, while the clinical significance of the p.Ile2541Val variant is uncertain, these data suggest that it is more likely to be benign. The ACMG/AMP Criteria applied: BP4. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 14, 2016	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Familial adenomatous polyposis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	11
Dann	Benign	0.67
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.28	N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.34	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.83	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.11
MVP		0.96
ClinPred		0.0044	T
GERP RS		0.87
Varity_R		0.028
gMVP		0.19

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: rs587778033; hg19: chr5-112178912; COSMIC: COSV57327926; COSMIC: COSV57327926;