Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001916423 | SCV002178020 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2021-05-02 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with breast cancer (PMID: 30287823). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces leucine with phenylalanine at codon 8 of the CDH1 protein (p.Leu8Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. |
| Ambry Genetics | RCV002449573 | SCV002734844 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-10-12 | criteria provided, single submitter | clinical testing | The p.L8F variant (also known as c.22C>T), located in coding exon 1 of the CDH1 gene, results from a C to T substitution at nucleotide position 22. The leucine at codon 8 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 4486 samples (8972 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105000 alleles tested) in our clinical cohort. This amino acid position is not well conserved on limited sequence alignment. 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 p.L8F remains unclear. |