rs879253782

Positions:

• chr5-112707523-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001407446.1(APC):​c.-195A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APC NM_001407446.1 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.40

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112707523-A-C is Pathogenic according to our data. Variant chr5-112707523-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 264670.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_001127511.3	c.-195A>C		5_prime_UTR_variant	1/14
APC	NM_001354895.2	c.-378A>C		5_prime_UTR_variant	1/16
APC	NM_001354897.2	c.-195A>C		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000507379.6	c.-195A>C		5_prime_UTR_variant	1/14	2
APC	ENST00000509732.6	c.-145A>C		5_prime_UTR_variant	1/16	4		P1
APC	ENST00000505350.2	c.-195A>C		5_prime_UTR_variant, NMD_transcript_variant	1/16	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2020

The c.-195A>C pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the APC gene. This mutation results from an A to C substitution 195 bases upstream from the first translated codon. This alteration has been described in a large family with clinical gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and completely segregated with disease in all 27 affected family members tested (Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). The alteration impacts a highly-conserved nucleotide within the YY1 binding motif of APC promoter 1B, and authors demonstrated disrupted protein binding associated with c.-195A>C. Furthermore, luciferase assay results showed significantly reduced promoter activity for this variant compared to wild type and APC allelic imbalance was observed in blood and GI tissue from affected individuals, supporting reduced in vivo expression from this allele. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879253782; hg19: chr5-112043220;