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]
  • See Evidence submitted by expert panel for details.

Variant: NM_004360.4(CDH1):c.387+1G>A

CA166072

141661 (ClinVar)

Gene: CDH1
Condition: hereditary diffuse gastric cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d06959f9-be16-41fc-a894-2c79db85ed90
Approved on: 2019-06-18
Published on: 2019-09-11

HGVS expressions

NM_004360.4:c.387+1G>A
NM_004360.4(CDH1):c.387+1G>A
NC_000016.10:g.68801894G>A
CM000678.2:g.68801894G>A
NC_000016.9:g.68835797G>A
CM000678.1:g.68835797G>A
NC_000016.8:g.67393298G>A
NG_008021.1:g.69603G>A
ENST00000261769.10:c.387+1G>A
ENST00000261769.9:c.387+1G>A
ENST00000422392.6:c.387+1G>A
ENST00000561751.1:c.154+1G>A
ENST00000562836.5:n.458+1G>A
ENST00000564676.5:n.669+1G>A
ENST00000564745.1:n.382+1G>A
ENST00000566510.5:c.387+1G>A
ENST00000566612.5:c.387+1G>A
ENST00000611625.4:c.387+1G>A
ENST00000612417.4:c.387+1G>A
ENST00000621016.4:c.387+1G>A
NM_004360.3:c.387+1G>A
NM_001317184.1:c.387+1G>A
NM_001317185.1:c.-1229+1G>A
NM_001317186.1:c.-1433+1G>A
NM_004360.5:c.387+1G>A
NM_001317184.2:c.387+1G>A
NM_001317185.2:c.-1229+1G>A
NM_001317186.2:c.-1433+1G>A
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Uncertain Significance

Met criteria codes 3
PVS1_Moderate BS2_Supporting PS3_Supporting
Not Met criteria codes 23
BA1 PP1 PP2 PP3 PP4 PM1 PM3 PM5 PM4 PM6 PM2 BS1 BS4 BS3 PS1 PS2 PS4 BP5 BP7 BP4 BP3 BP1 BP2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.387+1G>A variant is a canonical splice variant predicted to result in small in-frame amino acid deletions/insertions (PVS1_Moderate). This variant has an allele frequency of 0.00002 in gnomAD (4/245268) and is present with a frequency of 0.00012 (4/33552) in the Latino subpopulation (http://gnomad.broadinstitute.org). RT-PCR analysis demonstrated that this variant results in two additional in-frame transcripts, including a longer transcript with intronic retention of 57 bp and a shorter transcript with a 159 bp deletion (PS3_Supporting; https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20]). This variant has also been reported in at least three individuals not meeting HDGC clinical criteria (BS2_Supporting; https://ascopubs.org/doi/full/10.1200/PO.16.00021, https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20], PMID: 26845104). In summary, this variant is classified as a variant of uncertain significance based on conflicting ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Moderate, PS3_Supporting, BS2_Supporting.
Met criteria codes
PVS1_Moderate
This variant occurs at the canonical splice donor of exon 3 and has been shown experimentally to result in activation of a cryptic in-frame donor splice site (https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf, G20).
BS2_Supporting
This variant has been reported in an unaffected individual with a family history of breast and brain cancer who did not meet IGCLC criteria (https://ascopubs.org/doi/full/10.1200/PO.16.00021). The variant has also been reported in an unaffected individual at 41 years with a family history of breast cancer (https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf, G20) and in an individual with breast cancer at 60 years and no known cancer history in first-degree relatives (Shirts et al., 2016). This variant has also been observed in 5 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (SCV000573612.4, SCV000185111.5).
Reported in an individual with breast cancer at 60 years and no known cancer history in first-degree relatives. PubMed:26845104
PS3_Supporting
cDNA analysis of this variant through RT-PCR demonstrated that two additional in-frame transcripts are produced, including a longer transcript with intronic retention of 57 bp and a shorter transcript with a 159 bp deletion (https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf, G20).
Not Met criteria codes
BA1
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
PP2
Not applicable.
PP3
Not applicable.
PP4
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
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Not applicable.
PM4
Not applicable.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
This variant has an allele frequency of 0.00002 in gnomAD (4/245268) and 0.00001 in ExAC (1/119850). The allele is present exclusively in Latino subpopulations, with frequencies of 0.00012 (4/33552) in gnomAD and 0.00009 (1/11424) in ExAC.
BS1
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
Not applicable.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
BP7
Not applicable.
BP4
Not applicable.
BP3
Not applicable.
BP1
Not applicable.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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