ClinVar Genomic variation as it relates to human health

Not applicable criteria (PMID: 30311375)

Variant summary: CDH1 c.1370C>T (p.Thr457Met) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of 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 1.9e-05 in 1614058 control chromosomes, predominantly at a frequency of 0.00015 within the South Asian subpopulation in the gnomAD v4 database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1370C>T has been reported in the literature in at least one family affected with breast cancer (e.g., Garcia-Pelaez_2022), however without strong evidence for causality (e.g., lack of co-segregation data). This report therefore does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 36436516). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individual(s) with family history of breast cancer (Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 24728327, 15235021, 22850631, 36436516, 29641532)

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 457 of the CDH1 protein (p.Thr457Met). This variant is present in population databases (rs587778170, gnomAD 0.03%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 133845). 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 missense variant replaces threonine with methionine at codon 457 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 12/251482 chromosomes 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.

The p.T457M variant (also known as c.1370C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1370. The threonine at codon 457 is replaced by methionine, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 May;13:e0194098). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

CDH1: PM2:Supporting, BP4