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_004360.4(CDH1):c.1008G>T (p.Glu336Asp)

CA280990

18453 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f17d1590-599b-49d7-a1e0-273ed56fef12

HGVS expressions

NM_004360.4:c.1008G>T
NM_004360.4(CDH1):c.1008G>T (p.Glu336Asp)
NC_000016.10:g.68811859G>T
CM000678.2:g.68811859G>T
NC_000016.9:g.68845762G>T
CM000678.1:g.68845762G>T
NC_000016.8:g.67403263G>T
NG_008021.1:g.79568G>T
ENST00000261769.10:c.1008G>T
ENST00000261769.9:c.1008G>T
ENST00000422392.6:c.1008G>T
ENST00000561751.1:n.630G>T
ENST00000562836.5:n.1079G>T
ENST00000566510.5:c.852G>T
ENST00000566612.5:c.1008G>T
ENST00000611625.4:c.1008G>T
ENST00000612417.4:c.1008G>T
ENST00000621016.4:c.1008G>T
NM_004360.3:c.1008G>T
NM_001317184.1:c.1008G>T
NM_001317185.1:c.-608G>T
NM_001317186.1:c.-812G>T
NM_004360.5:c.1008G>T
NM_001317184.2:c.1008G>T
NM_001317185.2:c.-608G>T
NM_001317186.2:c.-812G>T
NM_004360.5(CDH1):c.1008G>T (p.Glu336Asp)

Likely Pathogenic

Met criteria codes 4
PS4_Supporting PS3 PM2_Supporting PVS1_Moderate
Not Met criteria codes 22
BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP4 BP5 BP7 PS2 PS1 PP4 PP1 PP2 PP3 BA1 PM6 PM3 PM4 PM5 PM1

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.1008G>T (p.Glu336Asp) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 9537325). Additionally, the variant has also been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). 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_Moderate, PM2_Supporting, PS3, PS4_Supporting.
Met criteria codes
PS4_Supporting
PMID: 9537325 1 family with DGC.
Multiple generation family with HDGC and variant. PubMed:9537325
PS3
PMID: 9537325- RT-PCR and sequencing shows activation of a cryptic splice site. Results in inclusion of 7bp from the intron. Will create an early STOP in exon 8.
PM2_Supporting
Based on ExAC, 1000 Genomes, or ESP.
PVS1_Moderate
G to non-G variants disrupting the last nucleotide of an exon.
Not Met criteria codes
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
PMID: 9537325- RT-PCR and sequencing shows activation of a cryptic splice site. Results in inclusion of 7bp from the intron. Will create an early STOP in exon 8.
BS1
Based on ExAC, 1000 Genomes, or ESP.
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
Splice predictors - all three predict loss of splice site; using PVS1_moderate instead
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
PMID: 9537325 1 family with DGC. Family in spreadsheet does not have details on GC being DGC, will not count.
PP1
One big family, multiple generations affected with DGC. Linkage analysis points to CDH1 gene, haplotype analysis shows it is found in affected, obligate carriers and some unaffected. Variant genotyped in 2 affected and 4 obligate carriers.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Splice predictors - all three predict loss of splice site; using PVS1_moderate instead
BA1
Based on ExAC, 1000 Genomes, or ESP.
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
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
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-08-28
Published on: 2023-08-28
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