Submissions for variant NM_000038.6(APC):c.715G>C (p.Ala239Pro)

dbSNP: rs777760565

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000204305	SCV003836571	benign	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.715G>C variant in APC is a missense variant predicted to cause substitution of alanine by proline at amino acid 239 (p.Ala239Pro). This variant has been observed in more than 35 heterozygous individuals with no features or family history of FAP, worth more than 10 healthy individual points (BS2; Ambry, Invitae internal data). The highest allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 0.0002269 in East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.00001) for BS1 (BS1). Finally, 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, BP1. (VCEP specifications version 1; date of approval 12/12/2022).
Invitae	RCV000204305	SCV000260792	uncertain significance	Familial adenomatous polyposis 1	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 239 of the APC protein (p.Ala239Pro). This variant is present in population databases (rs777760565, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 220329). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000564542	SCV000667445	likely benign	Hereditary cancer-predisposing syndrome	2021-10-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000204305	SCV000785054	uncertain significance	Familial adenomatous polyposis 1	2017-03-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564542	SCV001344820	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 239 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 4/251184 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153486	SCV003843396	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002228948	SCV004019789	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.