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
Final classification
Likely Benign
BS1BP2BP7
CDH1
c.1239C>T
p.Tyr413=
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_004360.5 · variants mapped to exon structure
CDH1
NM_004360.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
BS1
strong
review
Benign
Population frequency exceeds the CDH1 BS1 threshold of 0.1%. The highest observed frequency is 0.11215% in gnomAD v2.1 African/African American individuals and 0.16258% in gnomAD v4.1 African/African American individuals, both above the 0.1% cutoff.
gnomAD v2.1 African/African American AF 0.00112153 (28/24966)gnomAD v4.1 African/African American AF 0.0016258 (122/75040)gnomAD v4.1 grpmax FAF 0.00139058
BP2
supporting
review
Benign
This variant is observed in the homozygous state in gnomAD, which meets the CDH1 BP2 supporting rule. In gnomAD v4.1, 3 homozygotes are reported, all in the African/African American population.
gnomAD v4.1 homozygotes = 3African/African American homozygotes = 3
BP7
supporting
review
Benign
This is a synonymous variant, NM_004360.5:c.1239C>T (p.Tyr413=), located well within exon 9 rather than near the splice junction, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. This meets the CDH1 BP7 rule for synonymous variants outside the specified splice-region window.
Synonymous protein consequence NP_004351.1:p.(Tyr413=)Exon 9 position c.1239 is internal to the exonSpliceAI max delta score 0.01
Assessed · not applied
· 5 not met · 9 not assessed
Pathogenic
PVS1
This synonymous CDH1 variant does not fall into the CDH1 or generic PVS1 null-variant categories, and available evidence does not support loss of function through a canonical splice-site mechanism.
PS2
No de novo data with parental confirmation were identified for this variant.
PS3
No RNA assay demonstrating an abnormal CDH1 transcript was identified for this variant.
PS4
Available evidence does not document the number of families meeting CDH1 hereditary diffuse gastric cancer criteria for this variant.
PM2
This variant does not meet the CDH1 PM2_Supporting rarity threshold because it is present above 1 in 100,000 alleles overall and above 1 in 50,000 alleles in the African/African American population in both gnomAD v2.1 and v4.1.
PM6
No de novo occurrence without parental confirmation was identified for this variant.
PP1
No segregation data were identified for this variant.
PP3
Available computational evidence does not support an adverse splicing effect.
Benign
BA1
This variant does not reach the CDH1 BA1 stand-alone frequency threshold of 0.2%.
BS2
Although this variant is present in population databases, no dataset was identified showing the required number of individuals without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer and without family histories suggestive of HDGC.
BS3
No functional RNA study demonstrating no impact on CDH1 transcript composition was identified for this variant.
BS4
No segregation data showing lack of segregation with disease were identified.
BP4
Splicing prediction does not show a significant effect, with a SpliceAI maximum delta score of 0.01, but the evidence reviewed does not document the at least three concordant splicing predictors required for CDH1 BP4.
BP5
No alternate molecular explanation was identified that would support BP5 for this variant.
N/A · 11
PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6
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