chr16-68822081-C-T
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PM2_SupportingPS2PS4PP1_StrongPM5_SupportingPVS1
This summary comes from the ClinGen Evidence Repository: The c.1792C>T (p.Arg598*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This 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 >7 meioses observed across at least two families (PP1_Strong; PMID:21696387, 16061854, 11419427 and SCV000275702.5). This variant has also been reported in at least four families meeting HDGC clinical criteria (PS4_Strong; PMID:9751616, 21696387, 16061854, 11419427). There is one known de novo observation of this variant with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID:21696387). 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, PM2_Supporting, PP1_Strong, PS4, PS2, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA281000/MONDO:0007648/007
Frequency
Consequence
NM_001317186.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1792C>T | p.Arg598* | stop_gained | Exon 12 of 16 | ENST00000261769.10 | NP_004351.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727240
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several individuals with clinical histories consistent with Hereditary Diffuse Gastric Cancer (PMID: 9751616, 11419427, 11968084, 16061854, 18442100, 29589180); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9751616, 25525159, 23812922, 21424370, 30745422, 17545690, 11419427, 11968084, 15457549, 16061854, 18442100, 20373070, 21271559, 22524656, 22225527, 20233471, 19965908, 18788075, 29589180, 21696387) -
This nonsense variant causes the premature termination of CDH1 protein synthesis. In addition, it has been reported in individuals and families affected with breast and/or gastric cancer in the published literature (PMID: 21696387 (2012), 21271559 (2011), 18788075 (2008), 16061854 (2005), 11419427 (2001), 9751616 (1998)). Based on the available information, this variant is classified as pathogenic. -
CDH1: PVS1, PM2, PP1:Moderate, PS4:Moderate, PS2:Supporting -
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Hereditary diffuse gastric adenocarcinoma Pathogenic:6
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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PVS1; PS2; PS4; PM2; PP1_Strong (PMID: 30311375) -
This sequence change creates a premature translational stop signal (p.Arg598*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with gastric and/or breast cancer (PMID: 9751616, 11419427, 16061854, 18788075, 21271559, 21696387). ClinVar contains an entry for this variant (Variation ID: 12241). For these reasons, this variant has been classified as Pathogenic. -
The CDH1 p.Arg598* variant was identified in 7 of 112 proband chromosomes (frequency: 0.06) from families with hereditary diffuse gastric cancer (Huntsman 2001, Suriano 2005, Gayther 1998, Shah 2012). The variant was identified in dbSNP (rs121964877) as “with pathogenic, uncertain significance allele”, ClinVar (classified as pathogenic by a ClinGen expert panel (2018), Invitae, Ambry Genetics, GeneDx, and two other submitters). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The variant was also observed in a lobular breast cancer case in an HDGC family (Suriano 2005). The c.1792C>T variant leads to a premature stop codon at position 598, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CDH1 gene are an established mechanism of disease in hereditary diffuse gastric cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.R598* pathogenic mutation (also known as c.1792C>T), located in coding exon 12 of the CDH1 gene, results from a C to T substitution at nucleotide position 1792. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been observed in multiple hereditary diffuse gastric cancer (HDGC) kindreds (Gayther SA et al. Cancer Res. 1998 Sep 15;58(18):4086-9; Humar B et al. Hum Mutat. 2002 May;19(5):518-25; Pinheiro H et al. Hum. Mol. Genet. 2010 Mar;19:943-52; Suriano G et al. Clin. Cancer Res. 2005 Aug;11:5401-9), including one HDGC family in which the mutation was confirmed to be de novo (Shah MA et al. Clin. Genet. 2012 Sep;82:283-7). This alteration was also identified in 4 of 94 Maori individuals from New Zealand who were diagnosed with early onset diffuse gastric cancer (Hakkaart C et al. Fam. Cancer. 2019 01;18:83-90). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
This variant changes 1 nucleotide in exon 12 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with diffuse gastric cancer (PMID: 9751616, 11419427, 11968084, 16061854, 18788075, 19965908, 21696387, 28688938, 29589180) and lobular breast cancer (PMID: 18442100). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
The c.1792C>T (p.Arg598*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This 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 >7 meioses observed across at least two families (PP1_Strong; PMID: 21696387, 16061854, 11419427 and SCV000275702.5). This variant has also been reported in at least four families meeting HDGC clinical criteria (PS4_Strong; PMID: 9751616, 21696387, 16061854, 11419427). There is one known de novo observation of this variant with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID: 21696387). 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, PM2_Supporting, PP1_Strong, PS4, PS2, PM5_Supporting. -
Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at