Evidence Repository - Clinical Genome Resources

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

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

Curation Version - 2.1
Curation History
JSON LD for Version 2.1

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

Approved on: 2023-08-30

Published on: 2023-08-30

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

Pathogenic

PP1 PM2_Supporting PS3_Moderate PM5_Supporting PVS1_Strong PS4_Moderate

PP2 PP3 PP4 PM6 PM1 PM3 PM4 BS2 BS1 BS4 BS3 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2 BA1

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.

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

PM2_Supporting

Allele is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.

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

PM5_Supporting

Apply PM5_Supporting to the variant with the alteration at canonical splicing site.

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

PP2

Not applicable.

PP3

Not applicable.

PP4

Not applicable.

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

Not applicable.

PM3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM4

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

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

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

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

Curation History

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