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Variant: NM_004360.5(CDH1):c.1137+1G>A

CA10580104

233979 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8ce34bc3-a1c5-4a8f-b0a7-bacacf8a921a
Approved on: 2024-03-25
Published on: 2024-03-27

HGVS expressions

NM_004360.5:c.1137+1G>A
NM_004360.5(CDH1):c.1137+1G>A
NC_000016.10:g.68812264G>A
CM000678.2:g.68812264G>A
NC_000016.9:g.68846167G>A
CM000678.1:g.68846167G>A
NC_000016.8:g.67403668G>A
NG_008021.1:g.79973G>A
ENST00000261769.10:c.1137+1G>A
ENST00000261769.9:c.1137+1G>A
ENST00000422392.6:c.1137+1G>A
ENST00000562836.5:n.1208+1G>A
ENST00000565810.1:n.181+1G>A
ENST00000566510.5:c.981+1G>A
ENST00000566612.5:c.1137+1G>A
ENST00000611625.4:c.1137+1G>A
ENST00000612417.4:c.1137+1G>A
ENST00000621016.4:c.1137+1G>A
NM_004360.3:c.1137+1G>A
NM_001317184.1:c.1137+1G>A
NM_001317185.1:c.-479+1G>A
NM_001317186.1:c.-683+1G>A
NM_004360.4:c.1137+1G>A
NM_001317184.2:c.1137+1G>A
NM_001317185.2:c.-479+1G>A
NM_001317186.2:c.-683+1G>A

Pathogenic

Met criteria codes 5
PM5_Supporting PVS1_Strong PP1 PS3 PS4
Not Met criteria codes 21
BA1 BP5 BP7 BP2 BP3 BP4 BP1 BS2 BS3 BS4 BS1 PP4 PP3 PP2 PS2 PS1 PM3 PM1 PM4 PM6 PM2

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.1137+1G>A (NM_004360.5) variant in CDH1 occurs within the canonical splice donor site (+/- 1,2) of intron 8. It is predicted to cause a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_strong, PM5_Supporitng). The highest population minor allele frequency in gnomAD v 2.1.1 is (0.00008) (2/24,962 alleles) in the African/African American population which is >1/50,000 alleles, thus, criterion is not met (PM2_Supporting). The variant has been reported to segregate with diffuse gastric cancer in 3 affected meioses from 1 family that fulfills the clinical HDGC criteria (PP1; PMIDs 10477433). This variant has been reported in 9 probands meeting hereditary diffuse gastric cancer criteria (PS4; PMIDs 26182300, 10477433, ClinVar SCVs SCV000288420.8, SCV000278454.7, Internal lab contributors). 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, PS4, PS3, PM5_Supporting and PP1.
Met criteria codes
PM5_Supporting
This variant is predicted to cause a frame shift that is predicted to undergo NMD. Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
PVS1_Strong
The c.1137+1G>A (NM_004360.5) variant in CDH1 occurs within the canonical splice donor site (+/- 1,2) of intron 8. It is predicted to cause a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_strong, PM5_Supporitng). This prediction is confirmed by patient RNA data demonstrated that the variant impacts splicing by creating a frameshift (r.1055_1137del83 (p.G352VFS*7)) leading to a truncation at amino acid 358 (ClinVar SCV: SCV000278454.7, PS3). Insilico prediction tools predict loss of the donor splice.
PP1
The variant has been reported to segregate with diffuse gastric cancer in 3 affected meioses from 1 family that fulfils the clinical HDGC criteria (PP1); PMIDs 10477433.
PS3
Patient RNA data demonstrated that the variant impacts splicing by creating a frameshift (r.1055_1137del83 (p.G352VFS*7)) leading to a truncation at amino acid 358 (ClinVar SCV: SCV000278454.7, PS3).
PS4
This variant has been reported in 9 probands meeting hereditary diffuse gastric cancer criteria (PS4; PMIDs 26182300, 10477433, ClinVar SCVs SCV000288420.8, SCV000278454.7, Internal lab contributors). Two families meeting HDGC clinical criteria (PMID: 26182300, 10477433). Seven probands meeting HDGC criteria (SCV000288420.8, SCV000278454.7). 11 not meeting criteria (SCV000288420.8, SCV000278454.7, SCV000568305.4) PMID: 28195815 - removed as unclear if they meet criteira
Not Met criteria codes
BA1
The highest population minor allele frequency in gnomAD v 2.1.1 is (0.00008) (2/24,962 alleles) in the Africa/African American population which is >1/50,000 alleles, thus, criterion is not met (PM2_Supporting, BS1, and BA1 are not met)
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
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
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The highest population minor allele frequency in gnomAD v 2.1.1 is (0.00008) (2/24,962 alleles) in the Africa/African American population which is >1/50,000 alleles, thus, criterion is not met (PM2_Supporting, BS1, and BA1 are not met)
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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 : predicts a donor loss with a delta score of 0.99 MaxEntScan: Loss of donor site MaxEnt score 7.31 to -0.87 NNsplice: loss of donor splice, 0.99, to nothing Note: PP3 cannot be applied for canonical splice sites.
PP2
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
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v 2.1.1 is (0.00008) (2/24,962 alleles) in the Africa/African American population which is >1/50,000 alleles, thus, criterion is not met (PM2_Supporting, BS1, and BA1 are not met)
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