Submissions for variant NM_000038.6(APC):c.5981A>T (p.Asp1994Val)

gnomAD frequency: 0.00001  dbSNP: rs774815653

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227428	SCV000282789	benign	Familial adenomatous polyposis 1	2024-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571074	SCV000675863	likely benign	Hereditary cancer-predisposing syndrome	2020-05-18	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.
Counsyl	RCV000227428	SCV000785373	uncertain significance	Familial adenomatous polyposis 1	2017-08-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000571074	SCV000903336	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1994 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 been reported in an individual affected with colorectal cancer (PMID: 22669205). This variant has been identified in 4/281592 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	RCV001589165	SCV001825747	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with colon cancer (PMID: 22669205); This variant is associated with the following publications: (PMID: 18199528, 22669205)
Myriad Genetics, Inc.	RCV000227428	SCV004018988	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001589165	SCV004219618	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an affected individual with colorectal cancer (PMID: 22669205 (2012)). The frequency of this variant in the general population, 0.000085 (3/35408 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003998678	SCV004838132	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1994 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 been reported in an individual affected with colorectal cancer (PMID: 22669205). This variant has been identified in 4/281592 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.