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_004360.5(CDH1):c.2281G>A (p.Gly761Arg)

CA8130238

406676 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4a2d51fa-2fa9-42d8-828f-9a40df2ae757

Approved on: 2023-08-21

Published on: 2023-08-21

HGVS expressions

NM_004360.5:c.2281G>A

NM_004360.5(CDH1):c.2281G>A

NM_004360.5(CDH1):c.2281G>A (p.Gly761Arg)

NC_000016.10:g.68828290G>A

CM000678.2:g.68828290G>A

NC_000016.9:g.68862193G>A

CM000678.1:g.68862193G>A

NC_000016.8:g.67419694G>A

NG_008021.1:g.95999G>A

ENST00000261769.10:c.2281G>A

ENST00000261769.9:c.2281G>A

ENST00000422392.6:c.2098G>A

ENST00000562118.1:n.499G>A

ENST00000562836.5:n.2352G>A

ENST00000566510.5:c.*947G>A

ENST00000566612.5:c.*521G>A

ENST00000611625.4:c.2344G>A

ENST00000612417.4:c.1853+1736G>A

ENST00000621016.4:c.1866-5913G>A

NM_004360.3:c.2281G>A

NM_001317184.1:c.2098G>A

NM_001317185.1:c.733G>A

NM_001317186.1:c.316G>A

NM_004360.4:c.2281G>A

NM_001317184.2:c.2098G>A

NM_001317185.2:c.733G>A

NM_001317186.2:c.316G>A

Uncertain Significance

PS4_Moderate

BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP4 PP1 PP3 PP2 BA1 PM3 PM1 PM4 PM5 PM6 PM2 PVS1

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.2281G>A (p.Gly761Arg) variant has an allele frequency of 0.00006 (0.006%, 1/16,256 alleles) in the African gnomAD subpopulation (http://gnomad.broadinstitute.org). The variant has been identified in at least two families that meet HDGC clinical criteria (PS4_Moderate; internal laboratory collaborators). The variant has also been seen in three individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (internal laboratory collaborators); however, BS2 is not applied since more than 30% of reported individuals/family meet HDGC criteria. . In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PS4_Moderate.

PS4_Moderate

Two families that meet HDGC clinical criteria - One case of DGC diagnosed <40 years (Invitae) and two gastric cancer cases in a family, regardless of age, at least one confirmed DGC (Ambry).

BS2

Variant seen in three individual w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (Invitae, Ambry). Two families with family history of breast or gastric cancer with no information about pathology (Invitae). BS2 not met since more than 30% of reported individuals/family meet HDGC criteria.

BS4