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]
Link to SEPIO compliant JSON-LD document

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

CA16615353

406631 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 54dcc832-3023-40ec-9a6b-4f1a1a483159

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

Pathogenic

Met criteria codes 6
PP1 PS4_Moderate PS3_Moderate PVS1_Strong PM2_Supporting PM5_Supporting
Not Met criteria codes 20
PS2 PS1 PP4 PP3 PP2 PM3 PM1 PM4 PM6 BA1 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

Criteria Specification Approval History
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, 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.
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 two affected individuals from a family with HDGC. PubMed:15780560
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
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 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
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
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). To avoid overweighting the evidence toward pathogenicity, VCEP recommended downgrading PS3 to PS3_Moderate.
This variant was shown to alter splicing in a carrier with HDGC using RT-PCR. PubMed:17221870
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.
PM2_Supporting
Allele is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
Not applicable.
PP4
Not applicable.
PP3
Not applicable.
PP2
Not applicable.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
This variant was identified in two affected individuals from a family with HDGC. PubMed:15780560
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable.
BP4
Not applicable.
BP1
Not applicable.
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Not applicable.
Approved on: 2023-08-30
Published on: 2023-08-30
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