Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

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

Uncertain Significance

Met criteria codes 1
PS4_Moderate
Not Met criteria codes 25
BP5 BP7 BP4 BP3 BP1 BP2 PVS1 PS1 PS2 PS3 PP1 PP2 PP3 PP4 PM6 PM2 PM1 PM3 PM5 PM4 BA1 BS2 BS1 BS4 BS3

Evidence Links 0

Expert Panel

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.
Met criteria codes
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).
Not Met criteria codes
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
BP4
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
BP1
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No significant splicing alterations (HSF, MES)
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
>2/50,000 alleles: Global AF is 0.00001 (0.001%, 3/251,454 alleles). Max subpopulation AF is in African subpopulation with 0.00006 (1/16,256 alleles).
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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.
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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