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_004360.5(CDH1):c.387+1G>A

CA166072

141661 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d06959f9-be16-41fc-a894-2c79db85ed90

HGVS expressions

NM_004360.5:c.387+1G>A
NM_004360.5(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:n.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_004360.4: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

Uncertain Significance

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

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.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 (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PS3_Supporting, BS2_Supporting.
Met criteria codes
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
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).
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
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
Not applicable.
PM5
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.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
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
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Not applicable.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable.
BP4
Not applicable.
BP1
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
PS1
Not applicable.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
PP3
Not applicable.
PP2
Not applicable.
Approved on: 2023-08-21
Published on: 2023-08-21
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