Submissions for variant NM_000038.6(APC):c.5957C>T (p.Pro1986Leu)

gnomAD frequency: 0.00002  dbSNP: rs756266694

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003535730	SCV000552526	uncertain significance	Familial adenomatous polyposis 1	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1986 of the APC protein (p.Pro1986Leu). This variant is present in population databases (rs756266694, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of APC-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 411389). 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	RCV000573470	SCV000667524	likely benign	Hereditary cancer-predisposing syndrome	2020-09-22	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	RCV000475886	SCV000786261	uncertain significance	Familial adenomatous polyposis 1	2018-03-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573470	SCV000906649	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1986 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 reported in an individual affected with osteosarcoma with a truncation variant in FANCL (PMID: 26580448). This variant has been identified in 2/250354 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.
Baylor Genetics	RCV000475886	SCV001482686	uncertain significance	Familial adenomatous polyposis 1	2020-01-07	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000573470	SCV002536306	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-18	criteria provided, single submitter	curation
GeneDx	RCV003126748	SCV003803309	uncertain significance	not provided	2023-01-30	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; Observed in an individual with osteosarcoma who also harbored variants in other genes (Zhang et al., 2015); This variant is associated with the following publications: (PMID: 31395942, 18199528, 26580448)
Myriad Genetics, Inc.	RCV000475886	SCV004018385	uncertain significance	Familial adenomatous polyposis 1	2023-02-14	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479128	SCV004222886	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: APC c.5957C>T (p.Pro1986Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250354 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5957C>T has been reported in the literature in an individual affected with osteosarcoma (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26580448). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: seven submitters classified the variant as VUS while one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.