ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.223T>C (p.Phe75Leu)

dbSNP: rs587782193
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328219 SCV004035097 likely benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-18 reviewed by expert panel curation The c.223T>C (p.Phe75Leu) missense variant has a frequency of 0.000003977 (1 of 251,418) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.000008795 (1 of 113,700) in the Non-Finnish European population (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in at least 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_supporting, BS2.
Ambry Genetics RCV000130841 SCV000185739 likely benign Hereditary cancer-predisposing syndrome 2016-02-09 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 RCV000554536 SCV000637786 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-08-07 criteria provided, single submitter clinical testing 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 142040). This missense change has been observed in individual(s) with breast cancer (PMID: 31871109). This variant is present in population databases (rs587782193, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 75 of the CDH1 protein (p.Phe75Leu).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800438 SCV002046825 uncertain significance not provided 2021-04-01 criteria provided, single submitter clinical testing

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