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.687+2T>C

Curation Version - 3.0
Curation History
JSON LD for Version 3.0

CA396458165

463790 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8baa17b3-d7bd-464a-aea7-f82966a2d7a0

Approved on: 2024-02-26

Published on: 2024-03-28

HGVS expressions

NM_004360.4:c.687+2T>C

NM_004360.4(CDH1):c.687+2T>C

NC_000016.10:g.68808850T>C

CM000678.2:g.68808850T>C

NC_000016.9:g.68842753T>C

CM000678.1:g.68842753T>C

NC_000016.8:g.67400254T>C

NG_008021.1:g.76559T>C

ENST00000261769.10:c.687+2T>C

ENST00000261769.9:c.687+2T>C

ENST00000422392.6:c.687+2T>C

ENST00000561751.1:c.454+2T>C

ENST00000562836.5:n.758+2T>C

ENST00000566510.5:c.531+283T>C

ENST00000566612.5:c.687+2T>C

ENST00000567320.1:n.199T>C

ENST00000611625.4:c.687+2T>C

ENST00000612417.4:c.687+2T>C

ENST00000621016.4:c.687+2T>C

NM_004360.3:c.687+2T>C

NM_001317184.1:c.687+2T>C

NM_001317185.1:c.-929+2T>C

NM_001317186.1:c.-1133+2T>C

NM_004360.5:c.687+2T>C

NM_001317184.2:c.687+2T>C

NM_001317185.2:c.-929+2T>C

NM_001317186.2:c.-1133+2T>C

NM_004360.5(CDH1):c.687+2T>C

Uncertain Significance

PM2_Supporting PVS1_Strong PM5_Supporting BS2_Supporting

BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 PM3 PM1 PM4 PM6 BA1 BS4 BS3 BS1

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.687+2T>C variant is a canonical splice variant predicted to result in 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 is at +2 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). The variant has been observed in 6 individuals without DGC, SRC tumors or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting, BS2_Supporting.

PM2_Supporting

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

PVS1_Strong

This variant occurs at the canonical donor splice site of intron 5.

PM5_Supporting

GT-AG 1,2 acceptor/donor site variant with other Likely Pathogenic variants curated at the same splice site.

BS2_Supporting

The variant has been observed in 6 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (Laboratory internal data).

BP5

To our knowledge, this variant has not been observed in a case with a known molecular basis for disease.

BP7

BP7 does not apply to canonical splice variants.

BP2

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

BP3

BP3 does not apply to CDH1.

BP4

BP4 does not apply to canonical splice variants.

BP1

BP1 does not apply to canonical splice variants.

PS2

To our knowledge, this variant has not been observed de novo.

PS4

SCV000637846.1 - this family does not meet IGCLC criteria for HDGC.

PS3

To our knowledge, no functional studies for this variant have been reported.

PS1

PS1 does not apply to canonical splice variants.

PP4

PP4 does not apply to CDH1.

PP1

To our knowledge, segregation has not been reported.

PP3

PP3 does not apply to canonical splice variants. c.687+1G>A is also classified as likely pathogenic.

PP2

PP2 does not apply to canonical splice variants.

PM3

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

PM1

PM1 does not apply to CDH1.

PM4

PM4 does not apply to canonical splice variants.

PM6

To our knowledge, this variant has not been observed de novo.

BA1

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

BS4

To our knowledge, segregation has not been reported.

BS3

To our knowledge, no functional studies for this variant have been reported.

BS1

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

Curation History

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