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]

Variant: NM_004360.5(CDH1):c.1008G>A (p.Glu336=)

CA10580100

231647 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 03f19343-ea6f-460e-b6f5-a18145f32513
Approved on: 2024-03-25
Published on: 2024-03-27

HGVS expressions

NM_004360.5:c.1008G>A
NM_004360.5(CDH1):c.1008G>A (p.Glu336=)
NC_000016.10:g.68811859G>A
CM000678.2:g.68811859G>A
NC_000016.9:g.68845762G>A
CM000678.1:g.68845762G>A
NC_000016.8:g.67403263G>A
NG_008021.1:g.79568G>A
ENST00000261769.10:c.1008G>A
ENST00000261769.9:c.1008G>A
ENST00000422392.6:c.1008G>A
ENST00000561751.1:c.630G>A
ENST00000562836.5:n.1079G>A
ENST00000566510.5:c.852G>A
ENST00000566612.5:c.1008G>A
ENST00000611625.4:c.1008G>A
ENST00000612417.4:c.1008G>A
ENST00000621016.4:c.1008G>A
NM_004360.3:c.1008G>A
NM_001317184.1:c.1008G>A
NM_001317185.1:c.-608G>A
NM_001317186.1:c.-812G>A
NM_004360.4:c.1008G>A
NM_001317184.2:c.1008G>A
NM_001317185.2:c.-608G>A
NM_001317186.2:c.-812G>A
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Pathogenic

Met criteria codes 5
PS4 PS3 PP3 PVS1_Moderate PM2_Supporting
Not Met criteria codes 21
PS2 PS1 PP1 PP4 PP2 PM3 PM1 PM5 PM4 PM6 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP1 BP4

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.1008G>A (NM_004360.5) variant in CDH1is a G to non-G variant in the last nucleotide in exon 7. It is predicted to cause a loss of the donor splice site resulting in retention of intron 7 (PVS1_Moderate). This prediction is confirmed by RT-PCR cDNA demonstrating that the variant impacts splicing by producing 4 different alternatively spliced transcripts containing premature termination codons (PTC) caused by the use of cryptic donor splice sites in the intron (PS3, PMID: 8127895). This variant has been reported in 4 probands/families meeting hereditary diffuse gastric cancer genetic testing criteria (PS4; PMIDs 9536098, 27730413, ClinVar SCVs: SCV000275557.6, SCV000760854.3, Internal lab contributors). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The results from 3 in silico splicing predictors (SpliceAI, MaxEntScan, NNsplice) indicate that this variant may affect splicing by disrupting the donor splice site of intron 7 of CDH1 (PP3). 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, PP3.
Met criteria codes
PS4
This variant has been reported in 4 probands/families meeting hereditary diffuse gastric cancer genetic testing criteria (PS4; PMIDs 9536098, 27730413, ClinVar SCVs: SCV000275557.6, SCV000760854.3, Internal lab contributors).
PS3
RT-PCR cDNA demonstrated that the variant impacts splicing by producing 4 different alternatively spliced transcripts containing premature termination codons (PTC) caused by the use of cryptic donor splice sites in the intron (PMID: 8127895) (PS3).
PP3
The results from 3 in silico splicing predictors (SpliceAI, MaxEntScan, NNsplice) indicate that this variant may affect splicing by disrupting the donor splice site of intron 7 of CDH1 (PP3). SpliceAI: delta score of 0.88 MaxEntScan 5': Ref (c.1008G) 4.94 vs. c.1008G>A -4.38 NNSPLICE: Ref (c.1008G) donor site score: 0.65, abolished in c.1008G>A; potential double counting with PVS1 and PP3
PVS1_Moderate
The c.1008G>A (NM_004360.5) variant in CDH1is a G to non-G variant in the last nucleotide in exon 7. It is predicted to cause a loss of the donor splice site resulting in retention of intron 7 (PVS1_Moderate). This prediction is confirmed by RT-PCR cDNA demonstrated that the variant impacts splicing by producing 4 different alternatively spliced transcripts containing premature termination codons (PTC) caused by the use of cryptic donor splice sites in the intron (PMID: 8127895).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Proband with diffuse gastric dx via gastrectomy with family history of lobular breast cancer.
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
PM5
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
This variant is absent from gnomAD v2.1.1
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
Multiple authors independently verify KATO III (ATCC® HTB-103™) human gastric carcinoma cell line contains c.1008G>A and cDNA sequencing contains alternatively spliced transcripts containing premature termination codons (PTC).
BS1
This variant is absent from gnomAD v2.1.1
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
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
HSF prediction: Broken WT Donor Site; interpretation: Alteration of the WT donor site, most probably affecting splicing. MaxEntScan 5': Ref (c.1008G) 4.94 vs. c.1008G>A -4.38 NNSPLICE: Ref (c.1008G) donor site score: 0.65, abolished in c.1008G>A; not using since the CDH1 PVS1 rule in this case would require in silico modeling to predict splicing
Curation History
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