ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.49-2A>G

dbSNP: rs1060501226
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328344 SCV001142263 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-30 reviewed by expert panel curation The c.49-2A>G variant is a canonical splice variant predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed across at least two families (PP1; PMID: 17221870, 15780560). This variant has also been reported in at least three families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17221870, 15780560, 10072428). The c.49-2A>C allele was demonstrated to alter splicing through RT-PCR analysis of mRNA from an affected carrier (PS3_Moderate; PMID: 17221870). 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, PP1, PS4_Moderate, PS3_Moderate, PM5_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000462976 SCV000545400 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-02-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 406631). Disruption of this splice site has been observed in individual(s) with diffuse gastric cancer, lobular breast cancer, and colorectal cancer (PMID: 10072428, 17221870). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 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).
Ambry Genetics RCV002339140 SCV002642096 pathogenic Hereditary cancer-predisposing syndrome 2024-04-10 criteria provided, single submitter clinical testing The c.49-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the CDH1 gene. This alteration was originally reported in a family with six individuals from two successive generations affected with diffuse gastric cancer (Richards FM et al. Hum. Mol. Genet., 1999 Apr;8:607-10). It has later been reported in another family with diffuse gastric cancer (Moran CJ et al. Eur J Surg Oncol, 2005 Apr;31:259-64), as well as in an individual with lobular breast cancer (McVeigh TP et al. Clin. Breast Cancer, 2014 Apr;14:e47-51). 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. 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 pathogenic.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000462976 SCV003926826 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1_Strong; PS3_Moderate; PS4; PM2; PP1 (PMID: 30311375)
Myriad Genetics, Inc. RCV000462976 SCV004043261 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-08 criteria provided, single submitter clinical testing 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 has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15780560, 10072428, 24333020].
Baylor Genetics RCV003476030 SCV004210559 pathogenic Familial cancer of breast 2022-10-05 criteria provided, single submitter clinical testing
OMIM RCV000462976 SCV000033270 pathogenic Hereditary diffuse gastric adenocarcinoma 1999-04-01 no assertion criteria provided literature only

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