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]
Link to SEPIO compliant JSON-LD document

Variant: NM_004360.5(CDH1):c.1999del (p.Leu667fs)

CA191461

185252 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3fd5710b-0fc8-4a30-8a4d-c874a269f67b

HGVS expressions

NM_004360.5:c.1999del
NM_004360.5(CDH1):c.1999del (p.Leu667fs)
NC_000016.10:g.68823461del
CM000678.2:g.68823461del
NC_000016.9:g.68857364del
CM000678.1:g.68857364del
NC_000016.8:g.67414865del
NG_008021.1:g.91170del
ENST00000261769.10:c.1999del
ENST00000261769.9:c.1999del
ENST00000422392.6:c.1816del
ENST00000562118.1:n.217del
ENST00000562836.5:n.2070del
ENST00000566510.5:c.*665del
ENST00000566612.5:c.*239del
ENST00000611625.4:c.2062del
ENST00000612417.4:c.1830+1342del
ENST00000621016.4:c.1865+1307del
NM_004360.3:c.1999del
NM_001317184.1:c.1816del
NM_001317185.1:c.451del
NM_001317186.1:c.34del
NM_004360.4:c.1999del
NM_001317184.2:c.1816del
NM_001317185.2:c.451del
NM_001317186.2:c.34del

Pathogenic

Met criteria codes 4
PM2_Supporting PVS1 PS4_Moderate PM5_Supporting
Not Met criteria codes 22
PM6 PM3 PM1 PM4 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS3 PS1 PP4 PP1 PP3 PP2

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.1999del (p.Leu667fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least three families meeting HDGC clinical criteria (PS4_Moderate; SCV000329231.6, SCV000950815.1, SCV000215304.5). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting.
Met criteria codes
PM2_Supporting
Absent in gnomAD v2.1.1 in a region of sufficient coverage
PVS1
PTC created in exon 13 out of 16, which is expected to undergo NMD
PS4_Moderate
3 families fulfilling HDGC clinical criteria
PM5_Supporting
Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.
Not Met criteria codes
PM6
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
PM1
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
1 individual w/o DCG, SRC tumours, or LBC & whose family do not suggest HDGC
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
BS1
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
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
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
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
At least 1 affected meiosis (Ambry)
PP3
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
Approved on: 2023-08-25
Published on: 2023-08-25
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