ClinVar Genomic variation as it relates to human health

The c.370C>T (p.Arg124Cys) missense variant has a frequency of 0.039% in South Asians (12/30610 alleles) in the gnomAD v2.1.1 cohort. This variant has been observed in at least 10 (62) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; PMID: 30287823, SCV000288481.8, SCV000661624.3). 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): BS2.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 124 of the CDH1 protein (p.Arg124Cys). This variant is present in population databases (rs748086082, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 239905). 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 disruptive. 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.

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.

Variant summary: CDH1 c.370C>T (p.Arg124Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250704 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.370C>T has been reported in the literature as a VUS found in cases and unaffected controls in settings of multigene panel testing among germline and tumors of individuals with unspecified/bilateral breast cancer respectively (example, Momozawa_2018 Fountzilas_2016). These report(s) do not provide unequivocal conclusions about association of the variant with CDH1-related Hereditary Diffuse Gastric Cancer/Lobular Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, but also in unaffected controls (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 15235021, 30287823)

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.

Variant classified as Uncertain significance and reported on 11-03-2022 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Variant interpreted as Uncertain significance and reported on 01-24-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.