The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No CSPEC related information was provided by the message!

  • See Evidence submitted by expert panel for details.

Variant: NM_000038.6(APC):c.295C>T (p.Arg99Trp)

CA007948

135695 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 6e18394e-9b0b-45fb-8586-e6fa585186a5
Approved on: 2023-02-18
Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.295C>T
NM_000038.6(APC):c.295C>T (p.Arg99Trp)
NC_000005.10:g.112767263C>T
CM000667.2:g.112767263C>T
NC_000005.9:g.112102960C>T
CM000667.1:g.112102960C>T
NC_000005.8:g.112130859C>T
NG_008481.4:g.79743C>T
ENST00000257430.9:c.295C>T
ENST00000257430.8:c.295C>T
ENST00000507379.5:c.325C>T
ENST00000508376.6:c.295C>T
ENST00000508624.5:c.295C>T
ENST00000509732.5:c.295C>T
ENST00000512211.6:c.295C>T
NM_000038.5:c.295C>T
NM_001127510.2:c.295C>T
NM_001127511.2:c.325C>T
NM_001354895.1:c.295C>T
NM_001354896.1:c.295C>T
NM_001354897.1:c.325C>T
NM_001354898.1:c.220C>T
NM_001354899.1:c.295C>T
NM_001354900.1:c.118C>T
NM_001354901.1:c.118C>T
NM_001354902.1:c.325C>T
NM_001354903.1:c.295C>T
NM_001354904.1:c.220C>T
NM_001354905.1:c.118C>T
NM_001354906.1:c.-741C>T
NM_001127510.3:c.295C>T
NM_001127511.3:c.325C>T
NM_001354895.2:c.295C>T
NM_001354896.2:c.295C>T
NM_001354897.2:c.325C>T
NM_001354898.2:c.220C>T
NM_001354899.2:c.295C>T
NM_001354900.2:c.118C>T
NM_001354901.2:c.118C>T
NM_001354902.2:c.325C>T
NM_001354903.2:c.295C>T
NM_001354904.2:c.220C>T
NM_001354905.2:c.118C>T
NM_001354906.2:c.-741C>T
More

Benign

Met criteria codes 5
BS1 BS2 BP5 BP2 BP1
Not Met criteria codes 13
PM1 PM5 PM6 PVS1 BS4 BS3 BP7 PS2 PS3 PS1 PS4 PP4 PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The c.295C>T variant in APC is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid position 99 (p.Arg99Trp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency of the variant c.295C>T in gnomAD v2.1.1 (non-cancer) is 0.0007355 (95/129170 alleles) in the European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1 (BS1). This variant has been observed in heterozygous state in more than 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae and Ambry Genetics internal data). It has also been observed once in a homozygous state (Ambry Genetics internal data). This variant has been observed 4 times with other APC variants deemed (likely) pathogenic by the HCCP VCEP in individuals with FAP (BP2; PMIDs 23159591, 25604157, Bonn internal data). Finally, this variant has been observed in 6 patients with an alternate molecular basis for disease (BP5; Leiden University Medical Center internal data). 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, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022).
Met criteria codes
BS1
The highest population minor allele frequency of the variant c.295C>T in gnomAD v2.1.1 (non-cancer) is 0.0007355 (95/129170 alleles) in European (non-Finnish) population, which is higher than the InSiGHT ClinGen Hereditary Colorectal Cancer/Polyposis VCEP threshold (≥ 0.001%) for BS1, and therefore meets this criterion (BS1).
BS2
This variant has been observed in heterozygous state in more than 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae internal data, Ambry Genetics internal data). It has also been observed once in homozygous state (Ambry Genetics internal data).
BP5
This variant has been observed in 6 patient(s) with an alternate molecular basis for disease – co-occurrences observed with pathogenic variants in CHEK2, ATM, MSH6, BRCA1, MLH1, PTEN (BP5; Leiden University Medical Center internal data).
BP2
This variant has been observed in trans with the LoF variants (p.Ser1222Ter and large deletion of exon 15, respectively) in individuals with FAP (PMID: 23159591). Moreover, the variant was detected together with a LoF variant (c.1972_1975del;p.Glu658Thrfs*11) in a proband with multiple colorectal polyps, phase unknown (PMID: 25604157). Finally, This variant has been observed in an unknown phase with the variant c.646C>T, p. p.Arg216Ter (Bonn internal data) which is classified as Pathogenic by the InSiGHT ClinGen Hereditary Colorectal Cancer/ Polyposis Variant Curation Expert Panel in an individual with FAP.
BP1
APC is defined by the InSiGHT ClinGen Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1).
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant has been reported in 29 patients, with 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 0.5 points (PS4_variable not met, PMID11606402, GeneDX internal data, Leiden University Medical Centre internal data, Peter MacCallum Cancer Centre internal data, Bonn internal data, PMID11606402).
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.