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_004360.5(CDH1):c.163+4_163+6dup

CA194099

186186 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a79f4984-818c-4f25-a6dd-309d69774bd8

HGVS expressions

NM_004360.5:c.163+4_163+6dup
NM_004360.5(CDH1):c.163+4_163+6dup
NC_000016.10:g.68738415_68738417dup
CM000678.2:g.68738415_68738417dup
NC_000016.9:g.68772318_68772320dup
CM000678.1:g.68772318_68772320dup
NC_000016.8:g.67329819_67329821dup
NG_008021.1:g.6124_6126dup
ENST00000261769.10:c.163+4_163+6dup
ENST00000261769.9:c.163+4_163+6dup
ENST00000422392.6:c.163+4_163+6dup
ENST00000566510.5:c.163+4_163+6dup
ENST00000566612.5:c.163+4_163+6dup
ENST00000611625.4:c.163+4_163+6dup
ENST00000612417.4:c.163+4_163+6dup
ENST00000621016.4:c.163+4_163+6dup
NM_004360.3:c.163+4_163+6dup
NM_001317184.1:c.163+4_163+6dup
NM_001317185.1:c.-1453+4_-1453+6dup
NM_001317186.1:c.-1657+4_-1657+6dup
NM_004360.4:c.163+4_163+6dup
NM_001317184.2:c.163+4_163+6dup
NM_001317185.2:c.-1453+4_-1453+6dup
NM_001317186.2:c.-1657+4_-1657+6dup

Likely Benign

Met criteria codes 1
BS2
Not Met criteria codes 25
PS3 PS2 PS4 PS1 PVS1 PP4 PP1 PP3 PP2 BA1 PM1 PM3 PM4 PM5 PM6 PM2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The CDH1 c.163+4_163+6dupAGG variant occurs in the splice donor region of intron 2. This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in the gnomAD database (GRCh37) (http://gnomad.broadinstitute.org). This variant has been observed in more than ten individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000969083.1, SCV000216473.4, SCV000637738.2). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Met criteria codes
BS2
This variant was observed in 14 individuals without DGC, SRC tumours and whose families do not suggest HDGC (Ambry, GeneDx, Invitae). Note that this includes one individual with IDC and one reported gastric cancer in the family (Ambry) and one individual with no phenotypic information provided (GeneDx).
Not Met criteria codes
PS3
This variant has not been reported in the literature.
PS2
To our knowledge, this variant has not been reported as de novo in an individual with HDGC.
PS4
This variant was observed in 14 individuals without DGC, SRC tumours and whose families do not suggest HDGC (Ambry, GeneDx, Invitae). Note that this includes one individual with IDC and one reported gastric cancer in the family (Ambry) and one individual with no phenotypic information provided (GeneDx).
PS1
PS1 does not apply to this variant.
PVS1
PVS1 does not apply to this variant.
PP4
PP4 does not apply to CDH1.
PP1
Segregation information not available.
PP3
Some splice site predictors suggest this variant may increase splicing but this effect is not significant.
PP2
PP2 does not apply to CDH1.
BA1
This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in gnomAD (GRCh37). One in 10,684 alleles (0.00009360) and one in 22,176 alleles (0.00004509) within the East Asian and South Asian subpopulations, respectively.
PM1
PM1 does not apply to CDH1.
PM3
PM3 does not apply to CDH1.
PM4
PM4 does not apply to this variant.
PM5
PM5 does not apply to CDH1.
PM6
To our knowledge, this variant has not been reported as de novo in an individual with HDGC.
PM2
This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in gnomAD (GRCh37). One in 10,684 alleles (0.00009360) and one in 22,176 alleles (0.00004509) within the East Asian and South Asian subpopulations, respectively.
BS3
This variant has not been reported in the literature.
BS4
Segregation information not available.
BS1
This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in gnomAD (GRCh37). One in 10,684 alleles (0.00009360) and one in 22,176 alleles (0.00004509) within the East Asian and South Asian subpopulations, respectively.
BP2
To our knowledge, this variant has not been reported in cis or trans with a pathogenic variant in a family with HDGC.
BP3
BP3 does not apply to CDH1.
BP4
Some splice site predictors suggest this variant may increase splicing but this effect is not significant.
BP1
BP1 does not apply to CDH1.
BP5
To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.
BP7
BP7 does not apply to this variant.
Approved on: 2023-08-17
Published on: 2023-08-17
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