About CDH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDH1 c.1239C>T, p.(Tyr413=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen CDH1 VCEP v3.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Strong
BS1 · strong
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.
BP2Supporting
BP2 · supporting
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.
BP7Supporting
BP7 · supporting
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.
Recorded classification: 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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
150 / 1,614,116 alleles
gnomAD v4.1: 150 / 1,614,116 alleles. Recorded AF 9.29301e-05. Recorded homozygote count 3.
gnomAD 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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
14 reported laboratory submissions
9 Benign · 5 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen CDH1 VCEP v3.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 5 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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%.
In gnomAD v4.1, this variant is also observed in the homozygous state in 3 individuals, supporting BP2 under the CDH1 specification.
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.
No criteria match.
Met · 3
BS1 StrongPopulation 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. Details ▾Hide ▴
Rule
CDH1 BS1 uses a 0.1% MAF cutoff.
Evidence considered
- 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
Sources
BP2 SupportingThis 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. Details ▾Hide ▴
Rule
CDH1 BP2 Supporting can be applied when the variant is observed in the homozygous state in gnomAD.
Evidence considered
- gnomAD v4.1 homozygotes = 3
- African/African American homozygotes = 3
Sources
BP7 SupportingThis 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. Details ▾Hide ▴
Rule
CDH1 BP7 applies to synonymous and intronic variants at or beyond +7 to -21 locations; CDH1 does not require a conservation prediction.
Evidence considered
- Synonymous protein consequence NP_004351.1:p.(Tyr413=)
- Exon 9 position c.1239 is internal to the exon
- SpliceAI max delta score 0.01
Sources
Not met · 5 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
CDH1 PVS1 is applied per the modified CDH1 decision tree; this variant is outside the default null-variant buckets.
Evidence considered
- Synonymous variant NP_004351.1:p.(Tyr413=)
- Not a canonical +/-1
- 2 splice-site variant
- SpliceAI max delta score 0.01
Sources
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. Details ▾Hide ▴
Rule
CDH1 PM2_Supporting requires <=1 in 100,000 alleles overall and, if seen in >=2 individuals in a subpopulation, <=1 in 50,000 alleles in that subpopulation.
Evidence considered
- gnomAD v2.1 total AF 0.000134328 (38/282890)
- gnomAD v2.1 African/African American AF 0.00112153 (28/24966)
- gnomAD v4.1 total AF 0.0000929301 (150/1614116)
- gnomAD v4.1 African/African American AF 0.0016258 (122/75040)
Sources
PP3 Available computational evidence does not support an adverse splicing effect. SpliceAI shows a maximum delta score of 0.01, and the evidence reviewed does not document at least three concordant splicing predictors as required for CDH1 PP3. Details ▾Hide ▴
Rule
CDH1 PP3 requires at least three in silico splicing predictors in agreement, or the same splice-site logic for a well-characterized comparator variant.
Evidence considered
- SpliceAI DS_AG 0.00
- SpliceAI DS_AL 0.01
- SpliceAI DS_DG 0.00
- SpliceAI DS_DL 0.00
- Maximum delta score 0.01
Still missing
- Additional splicing predictor outputs beyond SpliceAI/Pangolin were not identified.
Sources
BA1 This variant does not reach the CDH1 BA1 stand-alone frequency threshold of 0.2%. The highest observed population frequency is 0.16258% in African/African American individuals in gnomAD v4.1, which is below the 0.2% cutoff. Details ▾Hide ▴
Rule
CDH1 BA1 uses a 0.2% MAF cutoff.
Evidence considered
- gnomAD v4.1 African/African American AF 0.0016258 (0.16258%)
- gnomAD v4.1 grpmax FAF 0.00139058
- gnomAD v2.1 African/African American AF 0.00112153 (0.11215%)
Sources
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. Details ▾Hide ▴
Rule
CDH1 BP4 requires at least three in silico splicing predictors in agreement.
Evidence considered
- SpliceAI max delta score 0.01
- Pangolin scores 0.0/-0.0
Still missing
- Additional concordant splicing predictor outputs were not identified.
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo data with parental confirmation were identified for this variant. Details ▾Hide ▴
PS3 No RNA assay demonstrating an abnormal CDH1 transcript was identified for this variant. Details ▾Hide ▴
Rule
CDH1 PS3 requires RNA evidence showing an abnormal out-of-frame or in-frame transcript.
Evidence considered
- No variant-specific functional RNA evidence identified
- OncoKB did not provide variant-specific functional data
Still missing
- Variant-specific RNA study evidence was not identified.
Sources
PS4 Available evidence does not document the number of families meeting CDH1 hereditary diffuse gastric cancer criteria for this variant. Details ▾Hide ▴
Rule
CDH1 PS4 requires one or more families meeting HDGC criteria, with strength based on family count.
Evidence considered
- ClinVar aggregate benign and likely benign submissions do not provide the family counts required for PS4
Still missing
- Family-level HDGC case counts were not identified.
Sources
PM6 No de novo occurrence without parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
CDH1 PM6 requires one or more de novo occurrences meeting the HDGC individual phenotype criteria without parental confirmation.
Evidence considered
- No PM6-qualifying de novo case information identified
Still missing
- Case-level de novo evidence without parental confirmation was not identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
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. Details ▾Hide ▴
Rule
CDH1 BS2 requires >=10 unaffected individuals for Strong or >=3 unaffected individuals for Supporting, with families not suggestive of HDGC.
Evidence considered
- Population database counts are available
- No phenotype-negative carrier series meeting CDH1 BS2 definitions identified
Still missing
- Phenotype-negative adult carrier data required by the CDH1 BS2 rule were not identified.
Sources
BS3 No functional RNA study demonstrating no impact on CDH1 transcript composition was identified for this variant. Details ▾Hide ▴
Rule
CDH1 BS3 requires functional RNA studies demonstrating no impact on transcript composition.
Evidence considered
- No variant-specific RNA assay showing normal transcript composition identified
Still missing
- Variant-specific benign RNA assay evidence was not identified.
Sources
BS4 No segregation data showing lack of segregation with disease were identified. Details ▾Hide ▴
BP5 No alternate molecular explanation was identified that would support BP5 for this variant. Details ▾Hide ▴
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 VCEPPS1 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks PS1 as not applicable
Sources
PM1 VCEPPM1 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks PM1 as not applicable
- No statistically significant hotspot was identified at Y413
Sources
PM3 VCEPPM3 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks PM3 as not applicable
Sources
PM4 N/APM4 is restricted to stop-loss variants in the CDH1 specification, and this variant is synonymous. Details ▾Hide ▴
Rule
Only apply to stop-loss variants.
Evidence considered
- Variant consequence NP_004351.1:p.(Tyr413=)
Sources
PM5 N/APM5 is repurposed in the CDH1 specification for truncating-variant logic and is not applicable to this synonymous variant. Details ▾Hide ▴
Rule
CDH1 PM5_Supporting is specified for nonsense, frameshift, and certain canonical splicing contexts rather than classic same-residue missense logic.
Evidence considered
- PM5 mode is gene-specific truncating logic
- No classic same-residue PM5 comparator review is applicable
Sources
cspec ↗pm5_candidates
PP2 VCEPPP2 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks PP2 as not applicable
Sources
PP4 VCEPPP4 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks PP4 as not applicable
Sources
PP5 VCEPPP5 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks PP5 as not applicable
Sources
BP1 VCEPBP1 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks BP1 as not applicable
Sources
BP3 VCEPBP3 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks BP3 as not applicable
Sources
BP6 VCEPBP6 is not applicable in the CDH1 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- CDH1 VCEP marks BP6 as not applicable
Sources
Identifiers
- Gene
- CDH1
- Transcript
- NM_004360.5
- Coding (HGVS c.)
- NM_004360.5:c.1239C>T
- Protein (HGVS p.)
- NP_004351.1:p.(Tyr413=)
- GRCh38
- chr16:68813414 C>T
- GRCh37
- chr16:68847317 C>T
- ClinVar
- 184347, 183812
Gene diagram
Every interpreted variant in CDH1, mapped onto the exon structure of NM_004360.5. Select a row to find it on the plot.
CDH1NM_004360.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CDH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
150 / 1,614,116 alleles
AF 9.29e-05 · 3 homozygotes · FAF 0.00139
gnomAD v2.1
38 / 282,890 alleles
AF 0.000134 · 0 homozygotes · FAF 0.000815
By genetic ancestry
gnomAD v4.1
AF 9.3e-05 · 150 / 1,614,116 alleles · 3 hom · FAF 0.0014
| African/African American122 / 75,040 | 0.00163 hom |
| Remaining individuals15 / 62,498 | 0.00024 |
| Admixed American10 / 60,014 | 0.00017 |
| European (non-Finnish)3 / 1,180,016 | 2.5e-06 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00013 · 38 / 282,890 alleles · 0 hom · FAF 0.00082
| African/African American28 / 24,966 | 0.0011 |
| Admixed American8 / 35,440 | 0.00023 |
| Remaining individuals1 / 7,224 | 0.00014 |
| European (non-Finnish)1 / 129,196 | 7.7e-06 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD 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.
gnomAD 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis 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. Details ▾Hide ▴
Rule
CDH1 BP7 applies to synonymous and intronic variants at or beyond +7 to -21 locations; CDH1 does not require a conservation prediction.
Evidence considered
- Synonymous protein consequence NP_004351.1:p.(Tyr413=)
- Exon 9 position c.1239 is internal to the exon
- SpliceAI max delta score 0.01
Sources
PP3 Available computational evidence does not support an adverse splicing effect. SpliceAI shows a maximum delta score of 0.01, and the evidence reviewed does not document at least three concordant splicing predictors as required for CDH1 PP3. Details ▾Hide ▴
Rule
CDH1 PP3 requires at least three in silico splicing predictors in agreement, or the same splice-site logic for a well-characterized comparator variant.
Evidence considered
- SpliceAI DS_AG 0.00
- SpliceAI DS_AL 0.01
- SpliceAI DS_DG 0.00
- SpliceAI DS_DL 0.00
- Maximum delta score 0.01
Still missing
- Additional splicing predictor outputs beyond SpliceAI/Pangolin were not identified.
Sources
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. Details ▾Hide ▴
Rule
CDH1 BP4 requires at least three in silico splicing predictors in agreement.
Evidence considered
- SpliceAI max delta score 0.01
- Pangolin scores 0.0/-0.0
Still missing
- Additional concordant splicing predictor outputs were not identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 15750927 ↗Decreased E-cadherin expression correlates with higher stage of Wilms' tumors.Safford SD et al. · 2005No paper-specific finding is recorded.
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PMID 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.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 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.No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007No paper-specific finding is recorded.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 22964825 ↗Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
150 / 1,614,116 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
9 Benign · 5 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637579
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/184347/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-68847317-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-68813414-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004360.5%3Ac.1239…
- OncoKB ↗www.oncokb.org/gene/CDH1/Y413=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDH1+c.1239C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
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
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.