Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_004360.4(CDH1):c.49-2A>G

CA16615353

406631 (ClinVar)

Gene: CDH1
Condition: hereditary diffuse gastric cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 54dcc832-3023-40ec-9a6b-4f1a1a483159
Approved on: 2019-03-22
Published on: 2019-09-11

HGVS expressions

NM_004360.4:c.49-2A>G
NM_004360.4(CDH1):c.49-2A>G
NC_000016.10:g.68738295A>G
CM000678.2:g.68738295A>G
NC_000016.9:g.68772198A>G
CM000678.1:g.68772198A>G
NC_000016.8:g.67329699A>G
NG_008021.1:g.6004A>G
ENST00000261769.10:c.49-2A>G
ENST00000261769.9:c.49-2A>G
ENST00000422392.6:c.49-2A>G
ENST00000566510.5:c.49-2A>G
ENST00000566612.5:c.49-2A>G
ENST00000611625.4:c.49-2A>G
ENST00000612417.4:c.49-2A>G
ENST00000621016.4:c.49-2A>G
NM_004360.3:c.49-2A>G
NM_001317184.1:c.49-2A>G
NM_001317185.1:c.-1567-2A>G
NM_001317186.1:c.-1771-2A>G
NM_004360.5:c.49-2A>G
NM_001317184.2:c.49-2A>G
NM_001317185.2:c.-1567-2A>G
NM_001317186.2:c.-1771-2A>G
More

Pathogenic

Met criteria codes 5
PP1 PS3_Moderate PM2 PVS1_Strong PS4_Moderate
Not Met criteria codes 21
BS2 BS1 BS4 BS3 PP2 PP3 PP4 PM1 PM3 PM5 PM4 PM6 PS1 PS2 BA1 BP5 BP7 BP4 BP3 BP1 BP2

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
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). The variant is absent in the gnomAD cohort (PM2; 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_Supporting; 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: PVS1_Strong, PM2, PP1_Supporting, PS4_Moderate, PS3_Moderate.
Met criteria codes
PP1
This variant was identified in five individuals with diffuse gastric cancer across two HDGC families (PMID: 17221870, 15780560). Total 3 meioses.
This variant was identified in three individuals with diffuse gastric cancer from a family with a history of gastric and extra-gastric cancers. PubMed:17221870
This variant was identified in two affected individuals from a family with HDGC. PubMed:15780560
PS3_Moderate
The c.49-2A>C allele was demonstrated to alter splicing through RT-PCR analysis of mRNA from an affected carrier (PMID: 17221870). Downgrade to moderate because PVS1_Strong has applied.
This variant was shown to alter splicing in a carrier with HDGC using RT-PCR. PubMed:17221870
PM2
Allele is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.
PVS1_Strong
This variant occurs at the canonical splice acceptor of intron 1 and is predicted to result in altered splicing with out-of-frame transcript.
PS4_Moderate
This variant has been identified in at least three HDGC families reported in the literature (PMID: 17221870, 15780560, 10072428).
This variant was identified in an individual with a personal and family history of diffuse gastric cancer. PubMed:10072428
This variant was identified in three individuals with diffuse gastric cancer from a family with a history of gastric and extra-gastric cancers. PubMed:17221870
This variant was identified in two affected individuals from a family with HDGC. Predictive genetic testing confirmed that four unaffected relatives aged 26-43 were carriers of the genetic variant and offered prophylactic total gastrectomy. PubMed:15780560
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
This variant was identified in three individuals with diffuse gastric cancer from a family with a history of gastric and extra-gastric cancers. PubMed:17221870
This variant was identified in two affected individuals from a family with HDGC. PubMed:15780560
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
Not applicable.
PP3
Not applicable.
PP4
Not applicable.
PM1
Not applicable.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Not applicable.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
Not applicable.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Not applicable.
BP4
Not applicable.
BP3
Not applicable.
BP1
Not applicable.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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