Submissions for variant NM_000038.6(APC):c.995G>A (p.Arg332Gln)

gnomAD frequency: 0.00004  dbSNP: rs377665107

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000200721	SCV003836575	benign	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.995G>A variant in APC is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 332 (p.Arg332Gln). This variant has been observed in heterozygous state in more than 100 healthy unrelated adult individuals worth more than 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data). The allele frequency of the c.995G>A variant in APC is 0.02% for the African sub-population (5/23604 alleles) in the non-cancer dataset from gnomAD (v2.1.1), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.001%) for BS1, and therefore meets BS1. 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 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022).
Ambry Genetics	RCV000167510	SCV000218368	likely benign	Hereditary cancer-predisposing syndrome	2020-06-18	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.
Invitae	RCV003316064	SCV000254053	uncertain significance	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 332 of the APC protein (p.Arg332Gln). This variant is present in population databases (rs377665107, 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: 187754). 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.
GeneDx	RCV000480823	SCV000569143	uncertain significance	not provided	2020-03-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27329244, 26917275)
Color Diagnostics, LLC DBA Color Health	RCV000167510	SCV000681942	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 332 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/282470 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.
Counsyl	RCV000200721	SCV000785636	uncertain significance	Familial adenomatous polyposis 1	2017-10-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000167510	SCV002529618	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003316064	SCV004019645	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.