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]

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Variant: NM_004360.5(CDH1):c.832+1G>A

CA396459027

463795 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cc34c30c-3789-40a7-9f1b-131a3a3bfb85

HGVS expressions

NM_004360.5:c.832+1G>A

NM_004360.5(CDH1):c.832+1G>A

NC_000016.10:g.68810342G>A

CM000678.2:g.68810342G>A

NC_000016.9:g.68844245G>A

CM000678.1:g.68844245G>A

NC_000016.8:g.67401746G>A

NG_008021.1:g.78051G>A

ENST00000261769.10:c.832+1G>A

ENST00000261769.9:c.832+1G>A

ENST00000422392.6:c.832+1G>A

ENST00000561751.1:c.455-1342G>A

ENST00000562836.5:n.903+1G>A

ENST00000566510.5:c.676+1G>A

ENST00000566612.5:c.832+1G>A

ENST00000611625.4:c.832+1G>A

ENST00000612417.4:c.832+1G>A

ENST00000621016.4:c.832+1G>A

NM_004360.3:c.832+1G>A

NM_001317184.1:c.832+1G>A

NM_001317185.1:c.-784+1G>A

NM_001317186.1:c.-988+1G>A

NM_004360.4:c.832+1G>A

NM_001317184.2:c.832+1G>A

NM_001317185.2:c.-784+1G>A

NM_001317186.2:c.-988+1G>A

Pathogenic

PS3 PVS1_Strong PS4_Moderate PM2_Supporting PM5_Supporting

BA1 BP2 BP5 BS2 BS3 BS1

Evidence Links 0

Expert Panel

CDH1 VCEP

Criteria Specification Information

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The CDH1 c.832+1G>A variant is a canonical splice variant in intron 6 predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent from the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in three families meeting IGCLC criteria for HDGC (PS4_Moderate, internal clinical lab data). This variant has also been reported in the literature in families with LBC who do not meet criteria for HDGC (PMID: 36436516, 32489267, 34643667). RNA analysis demonstrated two out-of-frame transcripts, r.754_832del79 p.(V252Efs*4) and r.688_832del145 p.(L230Efs*4) (PS3; internal clinical lab data). 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, PS3, PS4_Moderate, PM2_Supporting, PM5_Supporting.

PS3

RNA analysis demonstrated two abnormal out-of-frame transcripts, r.754_832del79 p.(V252Efs*4) and r.688_832del145 p.(L230Efs*4) (Ambry).

PVS1_Strong

This variant is at a canonical splice site, and therefore PVS1_Strong is applied.

PS4_Moderate

This variant was identified in three families meeting IGCLC criteria for HDGC (Invitae, Ambry, NCI). The variant was also observed in four families with DGC, LBC and/or SRC tumours who do not meet criteria for HDGC (Ambry, NCI; PMID: 36436516, 32489267, 34643667) and in two families without DGC, LBC and/or SRC tumours.

PM2_Supporting

This variant 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.

BA1

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

BP2

To our knowledge, this variant has not been reported in cis or trans with a pathogenic variant.

BP5

To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.

BS2

This variant was identified in three families meeting IGCLC criteria for HDGC (Invitae, Ambry, NCI). The variant was also observed in four families with DGC, LBC and/or SRC tumours who do not meet criteria for HDGC (Ambry, NCI) and in two families without DGC, LBC and/or SRC tumours.

BS3

RNA analysis demonstrated two abnormal out-of-frame transcripts, r.754_832del79 p.(V252Efs*4) and r.688_832del145 p.(L230Efs*4) (Ambry).

BS1

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

Approved on: 2024-03-25

Published on: 2024-03-27

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