Variant: NM_000038.6(APC):c.1242C>T (p.Arg414=)

CA026898

215553 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 48cfc76b-5e81-4be9-ab33-d77f9d6987ea

Approved on: 2023-02-18

Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.1242C>T
NM_000038.6(APC):c.1242C>T (p.Arg414=)
NC_000005.10:g.112819274C>T
CM000667.2:g.112819274C>T
NC_000005.9:g.112154971C>T
CM000667.1:g.112154971C>T
NC_000005.8:g.112182870C>T
NG_008481.4:g.131754C>T
ENST00000257430.9:c.1242C>T
ENST00000257430.8:c.1242C>T
ENST00000507379.5:c.1188C>T
ENST00000508376.6:c.1242C>T
ENST00000508624.5:c.*564C>T
ENST00000512211.6:c.1242C>T
NM_000038.5:c.1242C>T
NM_001127510.2:c.1242C>T
NM_001127511.2:c.1188C>T
NM_001354895.1:c.1242C>T
NM_001354896.1:c.1242C>T
NM_001354897.1:c.1272C>T
NM_001354898.1:c.1167C>T
NM_001354899.1:c.1158C>T
NM_001354900.1:c.1065C>T
NM_001354901.1:c.1065C>T
NM_001354902.1:c.969C>T
NM_001354903.1:c.939C>T
NM_001354904.1:c.864C>T
NM_001354905.1:c.762C>T
NM_001354906.1:c.393C>T
NM_001127510.3:c.1242C>T
NM_001127511.3:c.1188C>T
NM_001354895.2:c.1242C>T
NM_001354896.2:c.1242C>T
NM_001354897.2:c.1272C>T
NM_001354898.2:c.1167C>T
NM_001354899.2:c.1158C>T
NM_001354900.2:c.1065C>T
NM_001354901.2:c.1065C>T
NM_001354902.2:c.969C>T
NM_001354903.2:c.939C>T
NM_001354904.2:c.864C>T
NM_001354905.2:c.762C>T
NM_001354906.2:c.393C>T

Benign

• Met criteria codes: BS2 BS1 BP7 BP4

• Not Met criteria codes: PVS1 BA1 BS4 BS3 BP5 BP1 BP3 BP2 PS2 PS4 PS1 PS3 PP1 PP4 PP3 PP2 PM5 PM4 PM3 PM1 PM6 PM2

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The c.1242C>T (p.Arg414=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in heterozygous state in 11 healthy unrelated adult individuals worth 11 (≥ 10) healthy individual points in total (BS2; Ambry internal data). While RT-PCR from internal data demonstrated no impact of the variant on splicing (Ambry Internal Data), transcription assays (not otherwise specified) in the literature demonstrated that the variant impacts splicing by leading to partial exon 10 skipping (p.V313_Q412del) (PMID 20685668). Functional evidence was disregarded in the classification of this variant as they showed conflicting results. The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000034 (4/117512 alleles) in European (non-Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.00001) for BS1. 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, BP4, and BP7 (VCEP specifications version 1; date of approval: 12/12/2022).

Met criteria codes

• BS2: This variant has been observed in heterozygous state in 11 healthy unrelated adult individuals worth 11 (≥ 10) healthy individual points in total (BS2; Ambry internal data).
• BS1: The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000034 (4/117512 alleles) in European(non-Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (≥ 0.00001) for BS1.
• BP7: The c.1242C>T (p.Arg414=) variant is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP4, BP7).
• BP4: The results from 2 in silico splicing predictors SpliceAI and varSEAK support that this variant does not affect splicing (BP4).

Not Met criteria codes

• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: Not enough information re phenotype in Lagarde
• BS3: RT-PCR demonstrated no impact of the variant on splicing (BS3_Supporting, Ambry Internal Data). Additional details: high coverage, no aberrant splicing. Allele skewing not available in one patient analysed (other RNA samples not analysed at this time.
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: Synonymous variant
• BP3: Not used
• BP2: Not enough information re phenotype in Lagarde
• PS2: Not enough information re phenotype in Lagarde
• PS4: Not enough information re phenotype in Lagarde
• PS1: Do not use if the mechanism of pathogenicity for the reported variant is a splicing defect. The splicing defect was confirmed by RNA analysis.
• PS3: Transcription assays (not otherwise specified) demonstrated that the variant impacts splicing by leading to partial exon 9 skipping (p.V313_Q412del) (PMID20685668)(PS3_supporting).
• PP1: Not enough information re phenotype in Lagarde
• PP4: Not used
• PP3: see BP4
• PP2: Not used
• PM5: Do not use if the mechanism of pathogenicity for the reported variant is a splicing defect. The splicing defect was confirmed by RNA analysis.
• PM4: Not used
• PM3: Not used
• PM1: Not used
• PM6: Not enough information re phenotype in Lagarde
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline