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.164-4G>A

CA192317

185577 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e8ebbd96-aa4e-4e41-8cea-da0f5bf5f9f0

HGVS expressions

NM_004360.5:c.164-4G>A

NM_004360.5(CDH1):c.164-4G>A

NC_000016.10:g.68801666G>A

CM000678.2:g.68801666G>A

NC_000016.9:g.68835569G>A

CM000678.1:g.68835569G>A

NC_000016.8:g.67393070G>A

NG_008021.1:g.69375G>A

ENST00000261769.10:c.164-4G>A

ENST00000261769.9:c.164-4G>A

ENST00000422392.6:c.164-4G>A

ENST00000562836.5:n.235-4G>A

ENST00000564676.5:n.446-4G>A

ENST00000564745.1:n.159-4G>A

ENST00000566510.5:c.164-4G>A

ENST00000566612.5:c.164-4G>A

ENST00000611625.4:c.164-4G>A

ENST00000612417.4:c.164-4G>A

ENST00000621016.4:c.164-4G>A

NM_004360.3:c.164-4G>A

NM_001317184.1:c.164-4G>A

NM_001317185.1:c.-1452-4G>A

NM_001317186.1:c.-1656-4G>A

NM_004360.4:c.164-4G>A

NM_001317184.2:c.164-4G>A

NM_001317185.2:c.-1452-4G>A

NM_001317186.2:c.-1656-4G>A

Likely Benign

PM2_Supporting BS2 BP4

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

Evidence Links 0

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.164-4G>A (NM_004360.5) variant in CDH1 occurs in the splice donor region of intron 2. This variant has been observed in more than 10 individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; Ambry, GeneDx, Invitae). This variant occurs in one in 251,376 alleles in gnomAD 2.1.1 (less than one out of 100,000), within the European Non-Finnish population (one in 113,662 alleles) PM2_Supporting. In silico splice site predictors suggest that this variant does not impact splicing (BP4). However, splicing has not been assessed by in vitro assays. In summary, this variant meets the criteria to be classified as likely benign for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2, BP4. (CDH1 VCEP specifications version 3.1; 04/24/2023)

PM2_Supporting

This variant occurs in one in 251,376 alleles in gnomAD 2.1.1 (less than one out of 100,000), within the European Non-Finnish population (one in 113,662 alleles) PM2_Supporting.

BS2

This variant has been observed in 12 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; Ambry, GeneDx, Invitae). Note that this includes one individual with colorectal cancer and family history of gastric cancer NOS and one individual whose personal cancer history is not known.

BP4

This variant is not predicted to impact splicing.

PS2

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

PS4

This variant was identified in nine individuals without DGC, SRC tumours, LBC and whose families do not suggest HDGC (Ambry, GeneDx, Invitae). Note that this includes one individual with colorectal cancer and one reported gastric cancer NOS in the family (GeneDx).

PS3

Functional studies have not been reported for this variant.

PS1

PS1 does not apply to this variant.

BA1

This variant occurs in one in 251,376 alleles in gnomAD (GRCh37), within the European Non-Finnish population (one in 113,662 alleles).

PP4

PP4 does not apply to CDH1.

PP1

Not available.

PP3

This variant is not predicted to impact splicing.

PP2

PP2 does not apply to CDH1.

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.

PM6

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

PVS1

PVS1 does not apply to this variant.

BS4

Not available.

BS3

Functional studies have not been reported for this variant.

BS1

This variant occurs in one in 251,376 alleles in gnomAD (GRCh37), within the European Non-Finnish population (one in 113,662 alleles).

BP2

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

BP3

BP3 does not apply to CDH1.

BP1

BP1 does not apply to CDH1.

BP5

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

BP7

BP7 does not apply to this variant.

Approved on: 2023-08-02

Published on: 2023-08-02

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