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.387+5G>A

CA168422

142462 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 13ac5b7d-ad35-4b9b-a22d-b93011e6dd36

HGVS expressions

NM_004360.5:c.387+5G>A
NM_004360.5(CDH1):c.387+5G>A
NC_000016.10:g.68801898G>A
CM000678.2:g.68801898G>A
NC_000016.9:g.68835801G>A
CM000678.1:g.68835801G>A
NC_000016.8:g.67393302G>A
NG_008021.1:g.69607G>A
ENST00000261769.10:c.387+5G>A
ENST00000261769.9:c.387+5G>A
ENST00000422392.6:c.387+5G>A
ENST00000561751.1:n.154+5G>A
ENST00000562836.5:n.458+5G>A
ENST00000564676.5:n.669+5G>A
ENST00000564745.1:n.382+5G>A
ENST00000566510.5:c.387+5G>A
ENST00000566612.5:c.387+5G>A
ENST00000611625.4:c.387+5G>A
ENST00000612417.4:c.387+5G>A
ENST00000621016.4:c.387+5G>A
NM_004360.3:c.387+5G>A
NM_001317184.1:c.387+5G>A
NM_001317185.1:c.-1229+5G>A
NM_001317186.1:c.-1433+5G>A
NM_004360.4:c.387+5G>A
NM_001317184.2:c.387+5G>A
NM_001317185.2:c.-1229+5G>A
NM_001317186.2:c.-1433+5G>A

Benign

Met criteria codes 3
BP2_Strong BS3 BS2
Not Met criteria codes 23
PVS1 BA1 PS1 PS2 PS3 PS4 PP4 PP1 PP3 PP2 PM6 PM2 PM4 PM5 PM3 PM1 BS4 BS1 BP7 BP5 BP3 BP4 BP1

Evidence Links 2

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+5G>A variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000329224.7, SCV000288482.5, SCV000186607.5). This variant was also observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; SCV000288482.5). RNA studies demonstrated no abnormal splicing (BS3; PMID: 31642931). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BS3, BP2_Strong.
Met criteria codes
BP2_Strong
Invitae - One individual in her 50s homozygous for this variant (no DGC, LBC or SRC tumours).
BS3
RNA studies demonstrate no abnormal splicing (SCV000186607.5).
RNA studies demonstrate no abnormal splicing PubMed:31642931
BS2
GeneDx SCV000329224.7 - 14 probands, including unaffected (3) and those reporting a personal history of breast (3 IDC and 5 no pathology), and other cancers. No report of gastric cancer in probands or their family members. Invitae SCV000288482.5 - Observed in >50 individuals, with one individual in their 50s homozygous for this variant (no DGC, LBC or SRC tumours). No further details provided. Ambry SCV000186607.5 - seen 54 times (clinical details provided on 11 probands - no DGC, LBC or SRC tumours reported in 10 families, however stomach cancer reported in one family member).
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
PMID: 26123647 - This variant was found in a proband with nonsyndromic cleft lip with or without cleft palate from a non-familial case (no parental DNA available for testing whether it is a de novo variant) but not reported whether proband has DGC - does not meet IGCLC criteria.
This variant was found in a proband with nonsyndromic cleft lip with or without cleft palate from a non-familial case (no parental DNA available for testing whether it is a de novo variant) but not reported whether proband has DGC PubMed:26123647
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
From Alamut Visual - Predicted change at donor site 5 bps upstream: -27.6%. MaxEnt: -19.6%. NNSPLICE: -35.5%. SSF: -13.5%. Nucleotide conservation - PhastCons = 0.01 (conserved =1) and phyloP = 0.69. Not predicted to generate a cryptic splice site.
PP2
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
Observed in 0.0021% overall (6 of 281534 alleles). In African populations, observed in 0.016%, which is greater than 0.002%.
PM4
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
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
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
BP7
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
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
From Alamut Visual - Predicted change at donor site 5 bps upstream: -27.6%. MaxEnt: -19.6%. NNSPLICE: -35.5%. SSF: -13.5%. Nucleotide conservation - PhastCons = 0.01 (conserved =1) and phyloP = 0.69. Not predicted to generate a cryptic splice site.
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-08-10
Published on: 2023-08-10
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