Starting
Initialising…
0%
CDH1
Final classification
Likely Benign
CDH1 c.1138-3C>T · p.?
CDH1

The CDH1 NM_004360.5:c.1138-3C>T (NP_004351.1:p.?) variant has been reported in ClinVar with an expert panel classification of likely benign.

Gene
CDH1
Transcript
NM_004360.5
HGVS · transcript:coding
NM_004360.5:c.1138-3C>T
Consequence
N/A
GRCh38
chr16:68813310 C>T
GRCh37
chr16:68847213 C>T
Basis ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1 v3.1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong, BP2 supporting, BP6 supporting benign; combination = 1 strong benign + 1 supporting benign, which maps to Likely Benign. ▾
ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1 v3.1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong, BP2 supporting, BP6 supporting benign; combination = 1 strong benign + 1 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BP2BP6 Likely Benign
CDH1 c.1138-3C>T

The CDH1 NM_004360.5:c.1138-3C>T (NP_004351.1:p.?) variant has been reported in ClinVar with an expert panel classification of likely benign.1 This variant is present in population databases at a frequency above the CDH1 BS1 threshold, with the highest observed frequency in African/African American individuals of 0.16259% (122/75034) in gnomAD v4.1 and 0.11213% (28/24972) in gnomAD v2.1.2 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.3

BS1 + BP2 + BP6 → Likely Benign
1 clinvar ↗
2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗
3 spliceai ↗
Gene diagram · NM_004360.5 · variants mapped to exon structure
CDH1 NM_004360.5
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 9.41786e-05; MAF= 0.00942%, 152/1613954 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.00162593; MAF= 0.16259%, 122/75034 alleles, homozygotes = 3); grpmax FAF= 0.0013907.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 0.000130806; MAF= 0.01308%, 37/282862 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112126; MAF= 0.11213%, 28/24972 alleles, homozygotes = 0); grpmax FAF= 0.00081502.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0094% · 152 / 1,613,954
      3 hom · FAF 0.14%
      African/African American
      122 / 75,034
      0.16%
      3 hom
      Remaining individuals
      15 / 62,506
      0.024%
      Admixed American
      11 / 59,992
      0.018%
      European (non-Finnish)
      4 / 1,179,876
      0.00034%
      + 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
      gnomAD v2.1
      0.013% · 37 / 282,862
      0 hom · FAF 0.082%
      African/African American
      28 / 24,972
      0.11%
      Admixed American
      8 / 35,440
      0.023%
      Remaining individuals
      1 / 7,224
      0.014%
      + 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (7 clinical laboratories) and as Likely benign by Clingen Gastric Cancer Variant Curation Expert Panel (expert panel). (ClinVarID = 184346)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
      SpliceAI ↗
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Sources & reference links
      7Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Triaged references · 9 PMIDs not cited in assessment
      15322508 ↗ International variation. CLINVAR
      25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
      26123647 ↗ Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate. CLINVAR
      26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
      27978560 ↗ Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. CLINVAR
      28135145 ↗ Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. CLINVAR
      34242744 ↗ Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. CLINVAR
      15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR