Submissions for variant NM_004360.5(CDH1):c.213C>T (p.Leu71=)

gnomAD frequency: 0.00004  dbSNP: rs376667778

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163831	SCV000214417	likely benign	Hereditary cancer-predisposing syndrome	2015-03-29	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197237	SCV000253416	likely benign	Hereditary diffuse gastric adenocarcinoma	2025-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000421710	SCV000534288	likely benign	not specified	2016-11-28	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.
Color Diagnostics, LLC DBA Color Health	RCV000163831	SCV000908708	likely benign	Hereditary cancer-predisposing syndrome	2018-05-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284125	SCV001469747	likely benign	not provided	2020-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000421710	SCV002570765	likely benign	not specified	2022-07-23	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000197237	SCV003927003	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
Myriad Genetics, Inc.	RCV000197237	SCV005406537	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-12	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	RCV001354231	SCV001548793	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Leu71= variant was not identified in the literature nor was it identified in the Cosmic or Zhejiang University databases. The variant was identified in dbSNP (ID: rs376667778) as "With Likely benign allele" and ClinVar (classified as likely benign by Ambry Genetics, Invitae, and GeneDx). The variant was identified in control databases in 11 of 277092 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24018 chromosomes (freq: 0.00008), Other in 3 of 6466 chromosomes (freq: 0.0005), European in 5 of 126616 chromosomes (freq: 0.00004), Finnish in 1 of 25770 chromosomes (freq: 0.00004); it was not observed in the Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu71= 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 addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.