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]

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Variant: NM_001317186.2:c.-460G>A

CA288034

127912 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b815fbd2-a123-4504-8023-98f8e3c79c7e

Approved on: 2023-08-03

Published on: 2023-08-03

HGVS expressions

NM_001317186.2:c.-460G>A

NC_000016.10:g.68815554G>A

CM000678.2:g.68815554G>A

NC_000016.9:g.68849457G>A

CM000678.1:g.68849457G>A

NC_000016.8:g.67406958G>A

NG_008021.1:g.83263G>A

ENST00000261769.10:c.1360G>A

ENST00000261769.9:c.1360G>A

ENST00000422392.6:c.1177G>A

ENST00000562836.5:n.1431G>A

ENST00000566510.5:c.*26G>A

ENST00000566612.5:c.1360G>A

ENST00000611625.4:c.1423G>A

ENST00000612417.4:c.1360G>A

ENST00000621016.4:c.1360G>A

NM_004360.3:c.1360G>A

NM_001317184.1:c.1177G>A

NM_001317185.1:c.-189G>A

NM_001317186.1:c.-460G>A

NM_004360.4:c.1360G>A

NM_004360.5:c.1360G>A

NM_001317184.2:c.1177G>A

NM_001317185.2:c.-189G>A

NM_004360.5(CDH1):c.1360G>A (p.Val454Ile)

Likely Benign

BS2

BS3 BS1 BS4 PS3 PS2 PS4 BP5 BP2 BA1 PP3 PP1 PM2 PM6 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.1360G>A (p.Val454Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 4 in 152,164 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). 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. (CDH1 VCEP specifications version 3.1; 05/22/2023)

BS2

This variant has been observed in 155 families hot meeting IGCLC criteria for HDGC. This variant was also identified in one family with a history of unspecified gastric cancer and a proband with ILC in their 40s.

BS3

To our knowledge, splicing studies for this variant have not been reported.

BS1

This variant occurs at a frequency of 2.6x10-5 (4 in 152,164 alleles) in gnomAD.

BS4

To our knowledge, this variant has not been observed in an HDGC family.

PS3

To our knowledge, splicing studies for this variant have not been reported.

PS2

To our knowledge, this variant has not been observed in a proband meeting IGCLC criteria for HDGC.

PS4

BP5

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

BP2

To our knowledge, this variant has not been observed in a family meeting IGCLC criteria for HDGC.

BA1

This variant occurs at a frequency of 2.6x10-5 (4 in 152,164 alleles) in gnomAD.

PP3

This variant is not predicted to alter splicing.

PP1

To our knowledge, this variant has not been observed in an HDGC family.

PM2

This variant occurs at a frequency of 2.6x10-5 (4 in 152,164 alleles) in gnomAD.

PM6

To our knowledge, this variant has not been observed in a proband meeting IGCLC criteria for HDGC.

PM5

PM5 is not applicable for missense variants in CDH1.

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