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.1703C>G (p.Thr568Arg)

CA396465435

428619 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e931bff4-ef53-42d8-b30d-cfb0e477f7ce

HGVS expressions

NM_004360.5:c.1703C>G
NM_004360.5(CDH1):c.1703C>G (p.Thr568Arg)
NC_000016.10:g.68819417C>G
CM000678.2:g.68819417C>G
NC_000016.9:g.68853320C>G
CM000678.1:g.68853320C>G
NC_000016.8:g.67410821C>G
NG_008021.1:g.87126C>G
ENST00000261769.10:c.1703C>G
ENST00000261769.9:c.1703C>G
ENST00000422392.6:c.1520C>G
ENST00000562836.5:n.1774C>G
ENST00000566510.5:c.*369C>G
ENST00000566612.5:c.1566-2584C>G
ENST00000611625.4:c.1766C>G
ENST00000612417.4:c.1703C>G
ENST00000621016.4:c.1703C>G
NM_004360.3:c.1703C>G
NM_001317184.1:c.1520C>G
NM_001317185.1:c.155C>G
NM_001317186.1:c.-254-2584C>G
NM_004360.4:c.1703C>G
NM_001317184.2:c.1520C>G
NM_001317185.2:c.155C>G
NM_001317186.2:c.-254-2584C>G

Likely Pathogenic

Met criteria codes 3
PS3 PM2_Supporting PS4_Moderate
Not Met criteria codes 23
PS2 PS1 BA1 PP4 PP1 PP3 PP2 PM3 PM1 PM4 PM5 PM6 PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7

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.1703C>G (p.Thr568Arg) missense variant is absent in the gnomAD v2.1.1 cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in two probands meeting HDGC phenotype criteria (PS4_Moderate; SCV000580691.5). RNA data indicates abnormal splicing resulting in an abnormal out-of-frame transcript (PS3, internal lab contributor). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PS3, PS4_Moderate, PM2_Supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023)
Met criteria codes
PS3
This rule can only be applied to demonstrate splicing defects. RNA result from reference lab indicates abnormal splicing resulting in an abnormal out-of-frame transcript.
PM2_Supporting
Absent in gnomAD v2.1.1
PS4_Moderate
Two probands/families meeting HDGC criteria. (Note: would like double check on Ambry Proband 2)
Not Met criteria codes
PS2
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
BA1
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Do not use protein-based computational prediction models for missense variants. Variant is not predicted to impact splicing.
PP2
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
PM5
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
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
This rule can only be used to demonstrate lack of splicing and can only be applied to Synonymous, Intronic or Non-coding variants. BS3 may be downgraded based on quality of data.
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
Do not use protein-based computational prediction models for missense variants. Variant is not predicted to impact splicing.
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
Approved on: 2023-08-03
Published on: 2023-08-03
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