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.2430delT (p.Phe810Leufs)

CA197715

187464 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9eee2198-3726-4f14-81e7-c8c62c01506a

HGVS expressions

NM_004360.4:c.2430delT
NM_004360.4(CDH1):c.2430delT (p.Phe810Leufs)
NC_000016.10:g.68829788del
CM000678.2:g.68829788del
NC_000016.9:g.68863691del
CM000678.1:g.68863691del
NC_000016.8:g.67421192del
NG_008021.1:g.97497del
ENST00000261769.10:c.2430del
ENST00000261769.9:c.2430del
ENST00000422392.6:c.2247del
ENST00000562118.1:n.648del
ENST00000562836.5:n.2501del
ENST00000566510.5:c.*1096del
ENST00000566612.5:c.*670del
ENST00000611625.4:c.2493del
ENST00000612417.4:c.1853+3234del
ENST00000621016.4:c.1866-4415del
NM_004360.3:c.2430del
NM_001317184.1:c.2247del
NM_001317185.1:c.882del
NM_001317186.1:c.465del
NM_004360.4:c.2430del
NM_004360.5:c.2430del
NM_001317184.2:c.2247del
NM_001317185.2:c.882del
NM_001317186.2:c.465del
NM_004360.5(CDH1):c.2430del (p.Phe810fs)

Pathogenic

Met criteria codes 3
PS4 PM2_Supporting PVS1_Strong
Not Met criteria codes 23
BS3 BS4 BS1 BS2 BP7 BP5 BP3 BP1 BP4 BP2 PM6 PS3 PS1 PS2 BA1 PM1 PM4 PM5 PM3 PP2 PP3 PP4 PP1

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
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_Supporting; 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 (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4.
Met criteria codes
PS4
Variant reported in family with 3 cases of DGC, meeting IGCLC criteria. Unclear if all relatives had variant. Clinvar entry: This variant has been reported in at least three families affected with diffuse gastric cancer and gastric cancer (PMID: 26182300). Total 4 families.
Variant reported in one family where the proband had DGC at age 45. There were 3 cases total in the family, one of which was DGC (unclear if this is the proband). Family meets IGCLC criteria. PubMed:26182300
PM2_Supporting
Not in ExAC or GnomAD
PVS1_Strong
Frameshift variant and LOF is a known mechanism of disease in CDH1.
Not Met criteria codes
BS3
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
BS1
Not in ExAC or GnomAD
BS2
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
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
BP4
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
PM6
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Not in ExAC or GnomAD
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
PM3
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 code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Variant reported in one family where the proband had DGC at age 45. There were 3 cases total in the family, one of which was DGC (unclear if this is the proband). Family meets IGCLC criteria. PubMed:26182300
PP1
Variant present in unaffected proband. Brother had gastric cancer at age 33 (not clear if he carries variant) and father with variant had gastric cancer at age 56.
Approved on: 2023-08-29
Published on: 2023-08-29
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