ClinVar Genomic variation as it relates to human health

The c.532-1G>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is present once (1/245,906 alleles) in the gnomAD v2 cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Additionally, this variant has been reported in six families meeting HDGC clinical criteria (PS4; internal laboratory data). RNA analysis demonstrated that this variant results in an out-of-frame transcript, r.532_547del p.(I178Tfs*32) (PS3; internal laboratory data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4, PS3, PM5_Supporting.

This sequence change affects an acceptor splice site in intron 4 of the CDH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs771085839, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with clinical features of hereditary diffuse gastric cancer syndrome (PMID: 26556299; Invitae). ClinVar contains an entry for this variant (Variation ID: 406644). Studies have shown that disruption of this splice site results in partial skipping of exon 5 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (Palmer 2020); This variant is associated with the following publications: (PMID: 32427313)

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

This variant causes a G to C nucleotide substitution at the -1 position of intron 4 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with esophagogastric cancer in the literature (PMID: 26556299). This variant has been identified in 1/250964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

The c.532-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 5 of the CDH1 gene. This alteration was observed in 1 of 5054 African American women with breast cancer (Palmer JR et al. J Natl Cancer Inst, 2020 Dec;112:1213-1221). This alteration was also identified in an individual diagnosed with diffuse gastric cancer and colorectal cancer (Adib E et al. Br J Cancer, 2022 Mar;126:797-803). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.