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.1004G>A (p.Arg335Gln)

CA288013

127905 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7dbb5ff1-33fc-4e14-8d49-33515e45a9c8

HGVS expressions

NM_004360.5:c.1004G>A

NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln)

NC_000016.10:g.68811855G>A

CM000678.2:g.68811855G>A

NC_000016.9:g.68845758G>A

CM000678.1:g.68845758G>A

NC_000016.8:g.67403259G>A

NG_008021.1:g.79564G>A

ENST00000261769.10:c.1004G>A

ENST00000261769.9:c.1004G>A

ENST00000422392.6:c.1004G>A

ENST00000561751.1:c.626G>A

ENST00000562836.5:n.1075G>A

ENST00000566510.5:c.848G>A

ENST00000566612.5:c.1004G>A

ENST00000611625.4:c.1004G>A

ENST00000612417.4:c.1004G>A

ENST00000621016.4:c.1004G>A

NM_004360.3:c.1004G>A

NM_001317184.1:c.1004G>A

NM_001317185.1:c.-612G>A

NM_001317186.1:c.-816G>A

NM_004360.4:c.1004G>A

NM_001317184.2:c.1004G>A

NM_001317185.2:c.-612G>A

NM_001317186.2:c.-816G>A

Likely Benign

BS2

BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 BA1 PM6 PM2 PM3 PM1 PM4 PM5

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.1004G>A (p.Arg335Gln) missense variant has a maximum subpopulation frequency of 0.0085% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 140 probands not meeting HDGC phenotype criteria (BS2; SCV000149741.15, SCV000185512.7, SCV003926714.1, SCV000288411.10). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2.

BS2

>140 probands/families not meeting HDGC criteria (Invitae, GeneDx, Ambry)

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

This rule can only be used to demonstrate lack of splicing and can only be applied to Synonymous, Intronic or Non-coding variants.

BS1

Maximum subpopulation frequency = 0.008468%. This is less than MAF cutoff of 0.1% for BS1

BP5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP7

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

Do not use protein-based computational prediction models for missense variants.

BP1

Not applicable for CDH1.

PVS1

Missense variant

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

This rule can only be applied to demonstrate splicing defects.

PS1

Not applicable for CDH1.

PP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

Do not use protein-based computational prediction models for missense variants.

PP2

Not applicable for CDH1.

BA1

Maximum subpopulation frequency = 0.008468%. This is less than MAF cutoff of 0.2% for BA1

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

Present in 7 of 282636 alleles in gnomAD cohort. This is greater than requirement of <= one out of 100,000 alleles in gnomAD cohort.

PM3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

Not applicable for CDH1.

PM4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

Not applicable; PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant.

Approved on: 2023-09-25

Published on: 2023-09-27

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