Submissions for variant NM_000038.6(APC):c.420G>C (p.Glu140Asp)

dbSNP: rs202161017

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000409727	SCV003836600	likely benign	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.420G>C variant in APC is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 140 (p.Glu140Asp). APCis defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in heterozygous state in 67 healthy unrelated adult individuals worth more than 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data). This variant has also been observed in trans with a variant classified as (likely) pathogenic by the HCCP VCEP in an individual with FAP (BP2; Invitae Internal Data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022).
Counsyl	RCV000409727	SCV000488307	uncertain significance	Familial adenomatous polyposis 1	2016-02-24	criteria provided, single submitter	clinical testing
Invitae	RCV003534320	SCV000552524	likely benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579781	SCV000681655	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 140 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 breast cancer (PMID: 26976419). This variant has not been identified 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.
Ambry Genetics	RCV000579781	SCV001183752	likely benign	Hereditary cancer-predisposing syndrome	2023-06-02	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.
GeneDx	RCV000034414	SCV002006954	uncertain significance	not provided	2020-12-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV000409727	SCV004018818	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	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	RCV003317056	SCV004020542	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: APC c.420G>C (p.Glu140Asp) results in a 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 was absent in 251366 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.420G>C has been reported in the literature in at least one individual affected with breast cancer without strong evidence for causality (e.g., Tung_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26976419). Six ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. Four clinical diagnostic laboratories classified the variant as a variant of uncertain significance, while one clinical diagnostic laboratory and one expert panel classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000409727	SCV004209760	uncertain significance	Familial adenomatous polyposis 1	2022-07-31	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034414	SCV000043105	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.