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]

Link to SEPIO compliant JSON-LD document

Variant: NM_004360.5(CDH1):c.76G>C (p.Glu26Gln)

CA10580068

230669 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 708cdf45-b52a-42f5-8db0-407c60064452

HGVS expressions

NM_004360.5:c.76G>C

NM_004360.5(CDH1):c.76G>C (p.Glu26Gln)

NC_000016.10:g.68738324G>C

CM000678.2:g.68738324G>C

NC_000016.9:g.68772227G>C

CM000678.1:g.68772227G>C

NC_000016.8:g.67329728G>C

NG_008021.1:g.6033G>C

ENST00000261769.10:c.76G>C

ENST00000261769.9:c.76G>C

ENST00000422392.6:c.76G>C

ENST00000566510.5:c.76G>C

ENST00000566612.5:c.76G>C

ENST00000611625.4:c.76G>C

ENST00000612417.4:c.76G>C

ENST00000621016.4:c.76G>C

NM_004360.3:c.76G>C

NM_001317184.1:c.76G>C

NM_001317185.1:c.-1540G>C

NM_001317186.1:c.-1744G>C

NM_004360.4:c.76G>C

NM_001317184.2:c.76G>C

NM_001317185.2:c.-1540G>C

NM_001317186.2:c.-1744G>C

Uncertain Significance

BS2_Supporting PM2_Supporting

PM6 PM3 PM1 PM4 PM5 PVS1 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PP2

Evidence Links 0

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.76G>C (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Glu by Gln at amino acid 26 (p.Glu26Gln) in exon 2. This allele is absent from populations in gnomAD V2.1.1 (PM2_Supporting). This variant has been observed in at least three individuals without DGC, SRC tumours and LBC and whose families do not suggest HDGC (BS2_Supporting). This variant was reported in one individual with diffuse gastric cancer at 70 years without a family history of gastric cancer (PMID: 32241597). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023)

BS2_Supporting

This variant was identified in five individual without DGC, SRC tumours or LBC (BS2_Supporting; Invitae, Ambry). Note that this includes two individuals whose family history is not known. This variant was recently reported in the literature in an individual with DGC (tubular) in 70s without a family history of GC (DOI: 10.21203/rs.2.23340/v1).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting)

PM6

To our knowledge, this variant has not been reported as de novo in an individual with HDGC.

PM3

PM3 does not apply to CDH1.

PM1

PM1 does not apply to CDH1.

PM4

PM4 does not apply to this variant.

PM5

PM5 does not apply to CDH1.

PVS1

PVS1 does not apply to this variant.

BS4

Not available.

BS3

Functional studies for this variant have not been reported.

BS1

This variant is absent from gnomAD.

BP5

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

BP7

BP7 does not apply to this variant.

BP2

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

BP3

BP3 does not apply to CDH1.

BP4

Multiple splice site predictors do not suggest this variant impacts splicing.

BP1

BP1 does not apply to CDH1.

PS2

To our knowledge, this variant has not been reported as de novo in an individual with HDGC.

PS4

This variant was identified in one individual without DGC, SRC tumours or LBC but whose family history is unknown (Ambry). This variant was recently reported in the literature in an individual with DGC (tubular) in 70s without a family history of GC (DOI: 10.21203/rs.2.23340/v1).

PS3

Functional studies for this variant have not been reported.

PS1

No pathogenic missense variants have been reported at this position.

BA1

This variant is absent from gnomAD.

PP4

PP4 does not apply to CDH1.

PP1

Not available.

PP3

Multiple splice site predictors do not suggest this variant impacts splicing.

PP2

PP2 does not apply to CDH1.

Approved on: 2023-08-02

Published on: 2023-08-02

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