ClinVar Genomic variation as it relates to human health

The c.1565+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID: 26182300, SCV000149752.12 and internal laboratory contributor). This variant was also found to co-segregate with disease in multiple affected family members, with nine meioses observed across at least five families (PP1_Strong; SCV000149752.12 and internal laboratory contributor). The c.1565+1G>A allele was demonstrated to alter splicing through RNASeq analysis of mRNA from an affected carrier (PS3_Moderate; PMID: 31843900). 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, PS4, PP1_Strong, PS3_Moderate, PM2_Supporting.

This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 10 splice donor of the CDH1 gene. RNA studies have shown that this variant results in the use of a cryptic splice site, resulting in a 6 bp message insertion and premature stop at codon 523 (PMID: 31843900). This variant has been reported in individuals affected with breast and diffuse gastric cancer (PMID: 18046629, 24506336, 26182300, 26681312, 27064202, 27153395, 33322525; Lowstuter 2017, DOI: 10.1200/PO.16.00021). Different DNA subsitution variants at the +1 G nucleotide position have also been reported in individuals and families affected with diffuse gastric cancer (PMID: 11968084, 18788075, 26182300). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

PVS1_Strong; PS4_Moderate; PM2 (PMID: 30311375)

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in families with a history of cleft lip and palate in published literature (Green et al., 2022); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20373070, 25525159, 24506336, 27064202, 18046629, 27153395, 25986922, 26182300, 30745422, 26681312, 31986421, 30641862, 36436516, 34949788, 36246616)

This sequence change affects a donor splice site in intron 10 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with breast cancer and diffuse gastric cancer (PMID: 18046629, 26182300, 27064202, 27153395). ClinVar contains an entry for this variant (Variation ID: 127915). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

PVS1_STR, PS4_STR, PS3, PM2_SUP, PP1

_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP

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.

The c.1565+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 10 of the CDH1 gene. This mutation has been reported as pathogenic in a lobular breast cancer patient, whose family history was significant primarily for multiple breast cancers and also one early-onset gastric cancer (Schrader KA et al. Fam Cancer. 2008;7:73-82). In addition, a second splicing mutation at this position, c.1565+1G>T, has been detected in a diffuse gastric cancer family (Humar B et al. Hum Mutat. 2002;19(5):518-25). Of note, this mutation is also called IVS10+1G>A in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.

Variant interpreted as Pathogenic and reported on 07-15-2020 by Lab or GTR ID 61756. 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 Pathogenic and reported on 12-10-2015 by Lab Myriad. 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.

Variant interpreted as Pathogenic and reported on 09-30-2011 by Lab or GTR ID 61756. GenomeConnect- No Stomach for Cancer 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.