Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: APC vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000038.6(APC):c.422G>A (p.Arg141Lys)

CA16022245

824696 (ClinVar)

Gene: APC (HGNC:324)
Condition: familial adenomatous polyposis 1 (MONDO:0021056)
Inheritance Mode: Autosomal dominant inheritance
UUID: 393b5f9f-c4b7-4db7-a443-11d099ae1c2a
Approved on: 2025-05-19
Published on: 2025-05-19

HGVS expressions

NM_000038.6:c.422G>A
NM_000038.6(APC):c.422G>A (p.Arg141Lys)
NC_000005.10:g.112767390G>A
CM000667.2:g.112767390G>A
NC_000005.9:g.112103087G>A
CM000667.1:g.112103087G>A
NC_000005.8:g.112130986G>A
NG_008481.4:g.79870G>A
ENST00000502371.3:c.422G>A
ENST00000504915.3:c.422G>A
ENST00000505084.2:n.478G>A
ENST00000505350.2:c.*428G>A
ENST00000507379.6:c.452G>A
ENST00000509732.6:c.422G>A
ENST00000512211.7:c.422G>A
ENST00000257430.9:c.422G>A
ENST00000257430.8:c.422G>A
ENST00000507379.5:c.452G>A
ENST00000508376.6:c.422G>A
ENST00000508624.5:c.422G>A
ENST00000512211.6:c.422G>A
NM_000038.5:c.422G>A
NM_001127510.2:c.422G>A
NM_001127511.2:c.452G>A
NM_001354895.1:c.422G>A
NM_001354896.1:c.422G>A
NM_001354897.1:c.452G>A
NM_001354898.1:c.347G>A
NM_001354899.1:c.422G>A
NM_001354900.1:c.245G>A
NM_001354901.1:c.245G>A
NM_001354902.1:c.452G>A
NM_001354903.1:c.422G>A
NM_001354904.1:c.347G>A
NM_001354905.1:c.245G>A
NM_001354906.1:c.-614G>A
NM_001127510.3:c.422G>A
NM_001127511.3:c.452G>A
NM_001354895.2:c.422G>A
NM_001354896.2:c.422G>A
NM_001354897.2:c.452G>A
NM_001354898.2:c.347G>A
NM_001354899.2:c.422G>A
NM_001354900.2:c.245G>A
NM_001354901.2:c.245G>A
NM_001354902.2:c.452G>A
NM_001354903.2:c.422G>A
NM_001354904.2:c.347G>A
NM_001354905.2:c.245G>A
NM_001354906.2:c.-614G>A
More

Uncertain Significance

Met criteria codes 2
PM2_Supporting PVS1_Strong
Not Met criteria codes 1
BS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The NM_000038.6(APC):c.422G>A (p.Arg141Lys) variant in APC is a G to non-G change at the last nucleotide of exon 4. It is predicted to cause skipping of exon 4, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (List B; PVS1_Strong). However, exon skipping could not be confirmed by RTPCRSeq data. Even though this could be based on technical limitations, the variant allele was present in 35% of normally spliced reads, so the splicing impact seems to be low (internal data Ambry Genetics). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236810 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). The variant has been reported in three individuals without a colorectal cancer/polyposis associated phenotype (one person fulfills 0.5 points as a “healthy individual,” for the other two not enough information is available; BS2 not met; internal data Ambry Genetics). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PVS1_Strong and PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023).
Met criteria codes
PM2_Supporting
The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236810 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting).
PVS1_Strong
The NM_000038.6(APC):c.422G>A (p.Arg141Lys) variant in APC is a G to non-G change at the last nucleotide of exon 4. It is predicted to cause skipping of exon 4, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (List B; PVS1_Strong). However, exon skipping could not be confirmed by RTPCRSeq data. Even though this could be based on technical limitations, the variant allele was present in 35% of normally spliced reads, so the splicing impact seems to be low (internal data Ambry Genetics).
Not Met criteria codes
BS2
The variant has been reported in three individuals without a colorectal cancer/polyposis associated phenotype (one person fulfills 0.5 points as a “healthy individual,” for the other two not enough information is available; BS2 not met; internal data Ambry Genetics).
Curation History
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