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_004360.5(CDH1):c.832+1G>A

Curation Version - 3.0
Curation History
JSON LD for Version 3.0

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

Approved on: 2024-03-25

Published on: 2024-03-27

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

PS4_Moderate PM2_Supporting PVS1_Strong PM5_Supporting PS3

BS1 BS3 BS2 BP5 BP2 BA1

Evidence Links 0

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 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.

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.

PVS1_Strong

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

PM5_Supporting

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

PS3

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.

BS3

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

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.

BP5

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

BP2

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

BA1

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

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.