rs587781851

chr5-112841090-TAGAGTC-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_000038.6(APC):c.5501_5506del(p.Val1834_Arg1835del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000236 in 1,612,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1833R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: APC NM_000038.6 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1 O:1
• Conservation: PhyloP100: 4.38

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 -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000038.6.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.5501_5506del	p.Val1834_Arg1835del	inframe_deletion	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.5501_5506del	p.Val1834_Arg1835del	inframe_deletion	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152152 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: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000439 AC: 11 AN: 250850 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135572

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: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460618 Hom.: 0 AF XY: 0.0000261 AC XY: 19 AN XY: 726672

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This variant, c.5501_5506del, results in the deletion of 2 amino acid(s) of the APC protein (p.Val1834_Arg1835del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587778029, gnomAD 0.02%). This variant has been observed in individual(s) with colorectal cancer and/or multiple colorectal polyps (PMID: 25604157, 34347074; Invitae). ClinVar contains an entry for this variant (Variation ID: 141574). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 17, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 30, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 28, 2022	This variant causes an in-frame deletion of two amino acids in exon 16 of the APC protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with adenomatous polyps (PMID: 25604157), an individual with colorectal cancer (PMID: 34347074), as well as in a healthy individual (PMID: 24728327). This variant has been identified in 15/282250 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	clinical testing	Ambry Genetics	Jan 19, 2024	The c.5501_5506delTCAGAG variant (also known as p.V1834_R1835del), located in coding exon 15 of the APC gene,results from an in-frame deletion of 6 nucleotides at positions 5501 to 5506 and the removal of two well-conserved residues at codons 1834 and 1835. This alteration was detected in two affected siblings, one with 100 colorectal polyps and one with with colon cancer and polyps. In addition, this alteration was also detected in two unaffected relatives from this family, but was not detected in a third affected relative (Out AA et al. Fam. Cancer. 2015 Jun;14:247-57). This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 27, 2021	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 19, 2023	In the published literature, this variant has been reported in individuals with colorectal cancer and/or multiple polyps, with inconclusive segregation with disease in one family (PMIDs: 34347074 (2022), 25604157 (2015)). In addition, this variant has been reported in a healthy individual under the age of 50 (PMID: 24728327 (2014)), and observed to co-occur with a pathogenic variant in the APC gene in an individual in our internal patient population, suggesting it was not the primary cause of disease. The frequency of this variant in the general population, 0.00016 (5/30610 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	This variant is associated with the following publications: (PMID: 25604157) -

not specified Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2019	Variant summary: APC c.5501_5506delTCAGAG (p.Val1834_Arg1835del) results in an in-frame deletion that is predicted to remove 2 amino acids from the encoded protein. The variant allele was found at a frequency of 5.1e-05 in 276620 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5501_5506delTCAGAG has been reported in the literature in a family affected with Familial Adenomatous Polyposis, where this variant did not segregate with disease (Out_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778029; hg19: chr5-112176787;