Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000038.6(APC):c.1458T>C (p.Tyr486=)

CA005169

42238 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ceaf12ac-7838-446c-ae16-b4059d1b3f42

HGVS expressions

NM_000038.6:c.1458T>C

NM_000038.6(APC):c.1458T>C (p.Tyr486=)

NC_000005.10:g.112827157T>C

CM000667.2:g.112827157T>C

NC_000005.9:g.112162854T>C

CM000667.1:g.112162854T>C

NC_000005.8:g.112190753T>C

NG_008481.4:g.139637T>C

ENST00000257430.9:c.1458T>C

ENST00000257430.8:c.1458T>C

ENST00000502371.2:n.96+5166T>C

ENST00000504915.2:n.147T>C

ENST00000507379.5:c.1404T>C

ENST00000508376.6:c.1458T>C

ENST00000508624.5:c.*780T>C

ENST00000512211.6:c.1458T>C

NM_000038.5:c.1458T>C

NM_001127510.2:c.1458T>C

NM_001127511.2:c.1404T>C

NM_001354895.1:c.1458T>C

NM_001354896.1:c.1512T>C

NM_001354897.1:c.1488T>C

NM_001354898.1:c.1383T>C

NM_001354899.1:c.1374T>C

NM_001354900.1:c.1335T>C

NM_001354901.1:c.1281T>C

NM_001354902.1:c.1185T>C

NM_001354903.1:c.1155T>C

NM_001354904.1:c.1080T>C

NM_001354905.1:c.978T>C

NM_001354906.1:c.609T>C

NM_001127510.3:c.1458T>C

NM_001127511.3:c.1404T>C

NM_001354895.2:c.1458T>C

NM_001354896.2:c.1512T>C

NM_001354897.2:c.1488T>C

NM_001354898.2:c.1383T>C

NM_001354899.2:c.1374T>C

NM_001354900.2:c.1335T>C

NM_001354901.2:c.1281T>C

NM_001354902.2:c.1185T>C

NM_001354903.2:c.1155T>C

NM_001354904.2:c.1080T>C

NM_001354905.2:c.978T>C

NM_001354906.2:c.609T>C

Benign

BP4 BP7 BA1

PS3 PM2

Evidence Links 0

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP4, BP7 (VCEP specifications Version 1.0, date of approval: 12/12/2022).

BP4

The results from 2 in silico splicing predictors (SpliceAI and varSEAK) support that this variant does not affect splicing (BP4).

BP7

The c.1458T>C (p.Tyr486=)) variant (NM_000038.6)) is a synonymous (silent) variant that is not predicted by SpliceAI and VarSeak to impact splicing (BP4, BP7).

BA1

The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1).

PS3

Bioinformatics prediction suggested that this variant was likely a disease-causing polymorphism and may have induced the exon skipping of APC (PMID: 30272267). Using mini-gene system transfected into HeLa cells, the PCR product from the mutant mini-gene was smaller than that from the wild-type, which suggested that the mini-gene system encoding mutant induced the skipping of exon 12 in APC. However, this result does not meet the requirement to apply PS3 or modified PS3.

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-02-19

Published on: 2023-03-14

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