Submissions for variant NM_000038.6(APC):c.2780C>G (p.Ala927Gly)

gnomAD frequency: 0.00002  dbSNP: rs587781500

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129473	SCV000184243	benign	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV003650390	SCV000259601	uncertain significance	Familial adenomatous polyposis 1	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 927 of the APC protein (p.Ala927Gly). This variant is present in population databases (rs587781500, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30324682, 31159747). ClinVar contains an entry for this variant (Variation ID: 141108). 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	RCV000483264	SCV000566009	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with colorectal cancer and in an individual undergoing hereditary cancer panel testing (Iordache et al., 2018; Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 30324682)
Color Diagnostics, LLC DBA Color Health	RCV000129473	SCV000686912	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 927 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 been observed in individuals affected with colorectal cancer (PMID: 30324682), suspected hereditary cancer (31159747), or breast cancer (29684080). This variant has been identified in 5/250890 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.
GeneKor MSA	RCV000129473	SCV000821811	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779714	SCV000916469	uncertain significance	not specified	2018-04-16	criteria provided, single submitter	clinical testing	Variant summary: APC c.2780C>G (p.Ala927Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245756 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2e-05 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2780C>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000129473	SCV002538259	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-29	criteria provided, single submitter	curation
Baylor Genetics	RCV002514719	SCV004195705	uncertain significance	Familial adenomatous polyposis 1	2023-10-19	criteria provided, single submitter	clinical testing