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.1178T>A (p.Ile393Asn)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA294202

141828 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 002de39a-37d7-42dc-aa7b-2f386c531abf

Approved on: 2023-08-28

Published on: 2023-09-27

HGVS expressions

NM_004360.5:c.1178T>A

NM_004360.5(CDH1):c.1178T>A (p.Ile393Asn)

NC_000016.10:g.68813353T>A

CM000678.2:g.68813353T>A

NC_000016.9:g.68847256T>A

CM000678.1:g.68847256T>A

NC_000016.8:g.67404757T>A

NG_008021.1:g.81062T>A

ENST00000261769.10:c.1178T>A

ENST00000261769.9:c.1178T>A

ENST00000422392.6:c.1137+1090T>A

ENST00000562836.5:n.1249T>A

ENST00000565810.1:n.222T>A

ENST00000566510.5:c.1022T>A

ENST00000566612.5:c.1178T>A

ENST00000611625.4:c.1178T>A

ENST00000612417.4:c.1178T>A

ENST00000621016.4:c.1178T>A

NM_004360.3:c.1178T>A

NM_001317184.1:c.1137+1090T>A

NM_001317185.1:c.-438T>A

NM_001317186.1:c.-642T>A

NM_004360.4:c.1178T>A

NM_001317184.2:c.1137+1090T>A

NM_001317185.2:c.-438T>A

NM_001317186.2:c.-642T>A

Benign

BS2 BP2_Strong

PS1 PS4 PP2 PP3 PM1 PM3 PM4 PM2 PVS1 BA1 BS1 BP7 BP4 BP3 BP1

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 NM_004360.5(CDH1):c.1178T>A (p.Ile393Asn) variant has been observed in more than 10 (85) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant co-occurs in trans with a pathogenic CDH1 deletion in a carrier with a congenital malformation of the palate and family history of GC (BP2_Strong; internal laboratory contributors). This variant is known in one family with HDGC criteria (internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign based on BS2 and BP2_Strong. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong.

BS2

This variant has been observed in ~85 heterozygous individuals with no diffuse gastric cancer, signet ring cell carcinoma or lobular breast cancer and/or whose family histories do not suggest HDGC (BS2; GeneDX, Ambry, Invitae). Note that this includes two individuals with personal or family history of unspecified gastric cancer. One additional proband is known to have SRCC.

BP2_Strong

The NM_004360.5(CDH1):c.1178T>A (p.Ile393Asn) variant co-occurs in trans with a pathogenic CDH1 deletion in a carrier with personal history of palate congenital malformation and family history of gastric cancer (Ambry internal data).

PS1

Not applicable for CDH1

PS4

1 family meets HDGC criteria, however, that is less than 30% of all families carrying the NM_004360.5(CDH1):c.1178T>A (p.Ile393Asn) variant.

PP2

Not applicable for CDH1

PP3

Computational prediction models are not applicable for missense variants.

PM1

Not applicable for CDH1

PM3

Not applicable for CDH1

PM4

Not applicable for CDH1

PM2

Highest Minor Allele Frequency (MAFs): 2/24968; 0.00008; African sub-population.

PVS1

The NM_004360.5(CDH1):c.1178T>A (p.Ile393Asn) is a missense variant.

BA1

Highest Minor Allele Frequency (MAFs): 2/24968; 0.00008; African sub-population.

BS1

Highest Minor Allele Frequency (MAFs): 2/24968; 0.00008; African sub-population.

BP7

The NM_004360.5(CDH1):c.1178T>A (p.Ile393Asn) is a missense variant.

BP4

Computational prediction models are not applicable for missense variants.

BP3

Not applicable for CDH1

BP1

Not applicable for CDH1

Curation History

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