Submissions for variant NM_000038.6(APC):c.7531C>T (p.Leu2511Phe)

gnomAD frequency: 0.00004  dbSNP: rs72541815

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166364	SCV000217153	likely benign	Hereditary cancer-predisposing syndrome	2023-06-07	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	RCV000473143	SCV000552783	uncertain significance	Familial adenomatous polyposis 1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2511 of the APC protein (p.Leu2511Phe). This variant is present in population databases (rs72541815, gnomAD 0.004%). 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: 186722). 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	RCV000482783	SCV000566845	uncertain significance	not provided	2019-07-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000166364	SCV000681873	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-18	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 2511 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 5/282576 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	RCV000473143	SCV000785039	uncertain significance	Familial adenomatous polyposis 1	2017-03-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166364	SCV002528148	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002478515	SCV002778112	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2022-02-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000473143	SCV004017958	uncertain significance	Familial adenomatous polyposis 1	2023-02-16	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.