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]
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Variant: NM_004360.4(CDH1):c.2386dup (p.Arg796Profs)

CA723143791

12236 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 690b78a0-7ef7-4105-9b06-180bff60cf0c

HGVS expressions

NM_004360.4:c.2386dup
NM_004360.4(CDH1):c.2386dup (p.Arg796Profs)
NC_000016.10:g.68829744dup
CM000678.2:g.68829744dup
NC_000016.9:g.68863647dup
CM000678.1:g.68863647dup
NC_000016.8:g.67421148dup
NG_008021.1:g.97453dup
ENST00000261769.10:c.2386dup
ENST00000261769.9:c.2386dup
ENST00000422392.6:c.2203dup
ENST00000562118.1:n.604dup
ENST00000562836.5:n.2457dup
ENST00000566510.5:c.*1052dup
ENST00000566612.5:c.*626dup
ENST00000611625.4:c.2449dup
ENST00000612417.4:c.1853+3190dup
ENST00000621016.4:c.1866-4459dup
NM_004360.3:c.2386dup
NM_001317184.1:c.2203dup
NM_001317185.1:c.838dup
NM_001317186.1:c.421dup
NM_004360.5:c.2386dup
NM_001317184.2:c.2203dup
NM_001317185.2:c.838dup
NM_001317186.2:c.421dup
NM_004360.5(CDH1):c.2386dup (p.Arg796fs)

Likely Pathogenic

Met criteria codes 3
PS4_Supporting PVS1_Strong PM2_Supporting
Not Met criteria codes 23
PS1 PS3 PS2 BA1 PP3 PP2 PP4 PP1 PM5 PM1 PM4 PM3 PM6 BS2 BS3 BS4 BS1 BP3 BP4 BP1 BP2 BP7 BP5

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.2265T>A p.(Arg796Profs*11) variant is predicted to result in a premature stop codon that leads to a truncated protein (disrupting the last 87 amino acid residues of the CDH1 protein), and is located within the nonsense-mediated decay resistance region (downstream of aa 795) upstream of c.2506G>T p.(Glu836*) variant (PVS1_strong). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). 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 (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Supporting.
Met criteria codes
PS4_Supporting
Found in one family with diffuse gastric cancer - 2 of 3 variant carriers are affected (16 yo and 35 yo), while unaffected 34 yo (dad to 16 yo).
Found in one family with diffuse gastric cancer - 2 affected, both under 40 yo. PubMed:9537325
PVS1_Strong
Amino acid 795 is the last aa for invoking PVS1, because anything downstream is predicted to escape NMD. This variant is upstream of the most 3' pathogenic variant, which is c.2506G>T p.(Glu836*), therefore PVS1_strong is invoked. Other downstream truncating variants are: c.2398delC (p.Arg800Alafs) - pathogenic (ClinGen EP) - CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2, PS4, PP1 (co-segregation with disease). c.2430delT (p.Phe810Leufs) - pathogenic (ClinGen EP) - The c.2430delT (p.Phe810Leufs*6) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 26182300, SCV000261293.4, SCV000218032.4). 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: PVS1_Strong, PM2, PS4. c.2506G>T (p.Glu836*) - Pathogenic (ClinGen EP) - CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2, PS2 (de novo).
PM2_Supporting
Not observed in population database.
Not Met criteria codes
PS1
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
PS2
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
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
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
2 of 3 variant carriers affected with DGC - does not meet the criterion of 3-4 meioises.
2 of 3 variant carriers affected with DGC - does not meet the criterion of 3-4 meioises. PubMed:9537325
PM5
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
PM3
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
BS2
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
BS4
2 of 3 variant carriers affected with DGC - does not meet the criterion of 3-4 meioises. PubMed:9537325
BS1
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
BP2
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
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2024-03-28
Published on: 2024-03-28
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