The CDH1 NM_004360.5:c.1239C>T (p.Tyr413=, p.Y413=) variant has not been observed in COSMIC and has been reported in ClinVar predominantly as benign or likely benign.1 This variant is present in gnomAD above the CDH1 BS1 threshold of 0.1%, reaching 0.11215% in African/African American individuals in gnomAD v2.1 and 0.16258% in African/African American individuals in gnomAD v4.1, but it remains below the BA1 threshold of 0.2%.2 In gnomAD v4.1, this variant is also observed in the homozygous state in 3 individuals, supporting BP2 under the CDH1 specification.3 In silico splicing evidence does not support a splice-altering effect, with SpliceAI showing a maximum delta score of 0.01, which is consistent with applying BP7 for this synonymous internal exonic variant and does not support PP3.4
CDH1
Final classification
Likely Benign
CDH1 c.1239C>T · p.Tyr413=
CDH1
The CDH1 NM_004360.5:c.1239C>T (p.Tyr413=, p.Y413=) variant has not been observed in COSMIC and has been reported in ClinVar predominantly as benign or 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, BP7 supporting; combination = 1 strong benign + 2 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BP2BP7
Likely Benign
CDH1 c.1239C>T
BS1 + BP2 + BP7
→
Likely Benign
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
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 9.29301e-05; MAF= 0.00929%, 150/1614116 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0016258; MAF= 0.16258%, 122/75040 alleles, homozygotes = 3); grpmax FAF= 0.00139058.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000134328; MAF= 0.01343%, 38/282890 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112153; MAF= 0.11215%, 28/24966 alleles, homozygotes = 0); grpmax FAF= 0.00081502.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0093%
· 150 / 1,614,116
3 hom · FAF 0.14%
3 hom · FAF 0.14%
African/African American 122 / 75,040 |
0.16% 3 hom |
Remaining individuals 15 / 62,498 |
0.024% |
Admixed American 10 / 60,014 |
0.017% |
European (non-Finnish) 3 / 1,180,016 |
0.00025% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.013%
· 38 / 282,890
0 hom · FAF 0.082%
0 hom · FAF 0.082%
African/African American 28 / 24,966 |
0.11% |
Admixed American 8 / 35,440 |
0.023% |
Remaining individuals 1 / 7,224 |
0.014% |
European (non-Finnish) 1 / 129,196 |
0.00077% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 184347)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 10 PMIDs not cited in assessment
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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
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
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
22964825 ↗
Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR