Submissions for variant NM_000038.6(APC):c.1005A>G (p.Leu335=)

gnomAD frequency: 0.00006  dbSNP: rs3797704

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723617	SCV000109809	uncertain significance	not provided	2013-04-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764753	SCV000166011	benign	Familial adenomatous polyposis 1	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000077980	SCV000512061	benign	not specified	2015-07-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000491005	SCV000579801	likely benign	Hereditary cancer-predisposing syndrome	2015-11-24	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	RCV000491005	SCV000681439	benign	Hereditary cancer-predisposing syndrome	2016-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000077980	SCV000916488	benign	not specified	2017-12-11	criteria provided, single submitter	clinical testing	Variant summary: The APC c.1005A>G (p.Leu335Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts the creation of SRp40 binding site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 41/276982 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001962 (37/18854). This frequency is about 27 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant was reported in one breast patient but also in controls (Chang_2016) and also as a somatic occurrence (Chang_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077980	SCV001469894	benign	not specified	2019-12-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491005	SCV002534338	benign	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000077980	SCV004024359	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997193	SCV004837350	benign	Classic or attenuated familial adenomatous polyposis	2024-01-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003764753	SCV004931822	benign	Familial adenomatous polyposis 1	2024-02-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353629	SCV000591062	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Leu335Leu variant was identified in 3 of 384 proband chromosomes (frequency: 0.0078125) from Taiwense individuals or families with CRC or breast cancer (Chang YC 2016, Chang YS 2016). There was found to be no observed association between breast cancer risk and the variant (Chang YS 2016). The variant was also identified in dbSNP (ID: rs3797704) “With Likely benign,other allele”, ClinVar (with conflicting interpretations of pathogenicity; submitters: benign by Invitae and GeneDx, likely benign by Ambry Genetics and Department of Pathology and Laboratory Medicine (Sinai Health System), and uncertain significance by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics)), Clinvitae (4x), Cosmic (2x in carcinomas of the large intestine), and Zhejiang Colon Cancer Database (1x), but was not identified in Genesight-COGR. The variant was identified in control databases in 40 of 276782 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: European Non-Finnish in 1 of 126350 chromosomes (frequency: 0.000008), East Asian in 37 of 1854 chromosomes (frequency: 0.002), and European Finnish in 2 of 25792 chromosomes (frequency: 0.00008). The p.Leu335= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.