Submissions for variant NM_000038.6(APC):c.6131G>A (p.Ser2044Asn)

gnomAD frequency: 0.00003  dbSNP: rs375743017

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004564045	SCV000552443	uncertain significance	Familial adenomatous polyposis 1	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2044 of the APC protein (p.Ser2044Asn). This variant is present in population databases (rs375743017, 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: 411334). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV000571749	SCV000676361	likely benign	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Color Diagnostics, LLC DBA Color Health	RCV000571749	SCV000681783	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2044 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 APC-related disorders in the literature. This variant has been identified in 7/282214 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.
Eurofins Ntd Llc (ga)	RCV000733231	SCV000861272	uncertain significance	not provided	2018-05-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001912	SCV004838148	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2044 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 APC-related disorders in the literature. This variant has been identified in 7/282214 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.
GeneDx	RCV000733231	SCV005331864	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with osteosarcoma (PMID: 26580448); This variant is associated with the following publications: (PMID: 18199528, 26580448)