Variant: NM_000038.6(APC):c.220+1G>A

CA360617465

433598 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

UUID: b4c3c9f6-68c8-4734-96de-778a1063f875

Approved on: 2024-12-20

Published on: 2024-12-20

HGVS expressions

NM_000038.6:c.220+1G>A
NM_000038.6(APC):c.220+1G>A
NC_000005.10:g.112766411G>A
CM000667.2:g.112766411G>A
NC_000005.9:g.112102108G>A
CM000667.1:g.112102108G>A
NC_000005.8:g.112130007G>A
NG_008481.4:g.78891G>A
ENST00000502371.3:c.220+1G>A
ENST00000504915.3:c.220+1G>A
ENST00000505084.2:n.276+1G>A
ENST00000505350.2:c.*226+1G>A
ENST00000507379.6:c.250+1G>A
ENST00000509732.6:c.220+1G>A
ENST00000512211.7:c.220+1G>A
ENST00000257430.9:c.220+1G>A
ENST00000257430.8:c.220+1G>A
ENST00000507379.5:c.250+1G>A
ENST00000508376.6:c.220+1G>A
ENST00000508624.5:c.220+1G>A
ENST00000509732.5:c.220+1G>A
ENST00000512211.6:c.220+1G>A
NM_000038.5:c.220+1G>A
NM_001127510.2:c.220+1G>A
NM_001127511.2:c.250+1G>A
NM_001354895.1:c.220+1G>A
NM_001354896.1:c.220+1G>A
NM_001354897.1:c.250+1G>A
NM_001354898.1:c.145+1G>A
NM_001354899.1:c.220+1G>A
NM_001354900.1:c.43+1G>A
NM_001354901.1:c.43+1G>A
NM_001354902.1:c.250+1G>A
NM_001354903.1:c.220+1G>A
NM_001354904.1:c.145+1G>A
NM_001354905.1:c.43+1G>A
NM_001354906.1:c.-816+1G>A
NM_001127510.3:c.220+1G>A
NM_001127511.3:c.250+1G>A
NM_001354895.2:c.220+1G>A
NM_001354896.2:c.220+1G>A
NM_001354897.2:c.250+1G>A
NM_001354898.2:c.145+1G>A
NM_001354899.2:c.220+1G>A
NM_001354900.2:c.43+1G>A
NM_001354901.2:c.43+1G>A
NM_001354902.2:c.250+1G>A
NM_001354903.2:c.220+1G>A
NM_001354904.2:c.145+1G>A
NM_001354905.2:c.43+1G>A
NM_001354906.2:c.-816+1G>A

Pathogenic

• Met criteria codes: PS4_Supporting PM2_Supporting PVS1

• Not Met criteria codes: PS3 PP3

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The NM_000038.6:c.220+1G>A variant in APC occurs within the canonical splice donor site (+1) of intron 3. It is predicted to cause skipping of exon 3, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1). This prediction is confirmed by RNA analysis (internal data from Ambry Genetics and Invitae). This variant has been reported in one family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_supporting, [internal data from Ambry Genetics]). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PVS1, PS4_supporting and PM2_supporting applied (VCEP specifications v2.1.0; date of approval 11/24/2023).

Met criteria codes

• PS4_Supporting: This variant has been reported in one family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_supporting, internal data from Ambry Genetics]).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_supporting).
• PVS1: The NM_000038.6:c.220+1G>A variant in APC occurs within the canonical splice donor site (+1) of intron 3. It is predicted to cause skipping of exon 3, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• PS3: RNA analysis demonstrated that the variant impacts splicing by exon skipping [r.136_220del p.(Glu46Serfs*4)] (internal data from Ambry Genetics and Invitae). However, PS3_moderate cannot be applied since PVS1 is used.
• PP3: The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 3 of APC (PP3). However, PP3 cannot be applied, since PVS1 is used.