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]

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Variant: NM_000038.6(APC):c.995G>A (p.Arg332Gln)

CA016051

187754 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6c80822d-a69a-46c1-ada2-dc79abafcbf9

Approved on: 2023-02-18

Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.995G>A

NM_000038.6(APC):c.995G>A (p.Arg332Gln)

NC_000005.10:g.112819027G>A

CM000667.2:g.112819027G>A

NC_000005.9:g.112154724G>A

CM000667.1:g.112154724G>A

NC_000005.8:g.112182623G>A

NG_008481.4:g.131507G>A

ENST00000257430.9:c.995G>A

ENST00000257430.8:c.995G>A

ENST00000507379.5:c.941G>A

ENST00000508376.6:c.995G>A

ENST00000508624.5:c.*317G>A

ENST00000512211.6:c.995G>A

NM_000038.5:c.995G>A

NM_001127510.2:c.995G>A

NM_001127511.2:c.941G>A

NM_001354895.1:c.995G>A

NM_001354896.1:c.995G>A

NM_001354897.1:c.1025G>A

NM_001354898.1:c.920G>A

NM_001354899.1:c.911G>A

NM_001354900.1:c.818G>A

NM_001354901.1:c.818G>A

NM_001354902.1:c.964-242G>A

NM_001354903.1:c.934-242G>A

NM_001354904.1:c.859-242G>A

NM_001354905.1:c.757-242G>A

NM_001354906.1:c.146G>A

NM_001127510.3:c.995G>A

NM_001127511.3:c.941G>A

NM_001354895.2:c.995G>A

NM_001354896.2:c.995G>A

NM_001354897.2:c.1025G>A

NM_001354898.2:c.920G>A

NM_001354899.2:c.911G>A

NM_001354900.2:c.818G>A

NM_001354901.2:c.818G>A

NM_001354902.2:c.964-242G>A

NM_001354903.2:c.934-242G>A

NM_001354904.2:c.859-242G>A

NM_001354905.2:c.757-242G>A

NM_001354906.2:c.146G>A

Benign

BS2 BS1 BP1

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.995G>A variant in APC is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 332 (p.Arg332Gln). This variant has been observed in heterozygous state in >100 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data). The allele frequency of the c.995G>A variant in APC is 0.02% for the African sub-population (5/23604 alleles) in the non-cancer dataset from gnomAD (v2.1.1), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.001%) for BS1, and therefore meets BS1. APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). 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: BS1, BS2 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022).

BS2

This variant has been observed in heterozygous state in >100 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data).

BS1

The allele frequency of the c.420G>C (p.Glu140Asp) variant in APC is 0.02% for the African subpopulation (5/23604 allels) from gnomAD non-cancer dataset (v2.1.1), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold (≥ 0.001%) for BS1, and therefore meets this criterion (BS1).

BP1

APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP as a gene for which primarily truncating variants are known to cause disease (BP1).

PM2

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

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