About CDH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDH1 c.1138-3C>T, p.?
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. In gnomAD v4.1, the highest observed population frequency is 0.0016259 (0.16259%; 122/75034 alleles) in African/African American individuals, above the BS1 cutoff of 0.1%; the same threshold is also exceeded in gnomAD v2.1 at 0.0011213 (0.11213%; 28/24972 alleles).
BP2Supporting
BP2 · supporting
This variant is observed in the homozygous state in gnomAD, which supports BP2 at supporting strength under the CDH1 specification. In gnomAD v4.1, 3 homozygotes are present.
BP6Supporting
BP6 · supporting
Expert panel Clingen Gastric Cancer Variant Curation Expert Panel classified as Likely benign.
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, BP6 supporting benign; combination = 1 strong benign + 1 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
152 / 1,613,954 alleles
gnomAD v4.1: 152 / 1,613,954 alleles. Recorded AF 9.41786e-05. Recorded homozygote count 3.
gnomAD 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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
14 reported laboratory submissions
7 Likely benign · 7 Benign.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
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 · 4 not met · 10 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.1138-3C>T (NP_004351.1:p.?) variant has been reported in ClinVar with an expert panel classification of likely benign.
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.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.
No criteria match.
Met · 3
BS1 StrongPopulation frequency exceeds the CDH1 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.0016259 (0.16259%; 122/75034 alleles) in African/African American individuals, above the BS1 cutoff of 0.1%; the same threshold is also exceeded in gnomAD v2.1 at 0.0011213 (0.11213%; 28/24972 alleles). Details ▾Hide ▴
Rule
MAF cutoff of 0.1% with subpopulation size and allele-count requirements.
Evidence considered
- gnomAD v4.1 AFR AF 0.0016259 with AC 122 and AN 75034.
- gnomAD v2.1 AFR AF 0.0011213 with AC 28 and AN 24972.
Sources
BP2 SupportingThis variant is observed in the homozygous state in gnomAD, which supports BP2 at supporting strength under the CDH1 specification. In gnomAD v4.1, 3 homozygotes are present. Details ▾Hide ▴
Rule
Observed in the homozygous state in gnomAD.
Evidence considered
- gnomAD v4.1 homozygotes = 3.
Sources
BP6 SupportingExpert panel Clingen Gastric Cancer Variant Curation Expert Panel classified as Likely benign. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PVS1 This intronic variant is at c.1138-3, outside the canonical ±1,2 splice positions, and the variant-level PVS1 assessment does not place it in a qualifying loss-of-function category. Available computational evidence also does not suggest a major splice disruption, so PVS1 is not applied. Details ▾Hide ▴
Rule
Per modified CDH1 PVS1 decision tree.
Evidence considered
- CDH1 PVS1 is eligible at the gene level
- but this variant is not in a qualifying PVS1 bucket.
- SpliceAI max delta score 0.01.
Still missing
- Variant-specific RNA data would be needed to show an abnormal transcript if loss-of-function splicing is suspected.
Sources
PM2 Population frequency is above the CDH1 PM2 threshold. In gnomAD v4.1, the total allele frequency is 0.0000942 (152/1613954), above the required threshold of ≤0.00001, and the African/African American subpopulation frequency is 0.0016259 (122/75034), far above the ≤0.00002 subpopulation threshold when multiple alleles are present. Details ▾Hide ▴
Rule
≤1 out of 100,000 alleles in gnomAD; if present in ≥2 individuals within a subpopulation, ≤1 out of 50,000 alleles.
Evidence considered
- gnomAD v4.1 total AF 0.0000942
- AFR AF 0.0016259.
- gnomAD v2.1 total AF 0.0001308
- AFR AF 0.0011213.
Sources
BA1 Population frequency does not reach the CDH1 BA1 threshold. The highest observed gnomAD v4.1 population frequency is 0.0016259 (0.16259%) in African/African American individuals, which is below the BA1 cutoff of 0.2%. Details ▾Hide ▴
Rule
MAF cutoff of 0.2%.
Evidence considered
- gnomAD v4.1 AFR AF 0.0016259.
- gnomAD v2.1 AFR AF 0.0011213.
Sources
BP7 This intronic variant is at c.1138-3, which is not at or beyond the CDH1 BP7 intronic positions of +7 or -21, so BP7 is not applied. Details ▾Hide ▴
Rule
Synonymous and intronic variants at or beyond +7 to -21 locations.
Evidence considered
- Variant position is c.1138-3.
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo observation meeting the CDH1 phenotype-specific requirements was identified. Details ▾Hide ▴
Rule
One or more patients meeting HDGC individual phenotype criteria with parental confirmation.
Evidence considered
- No de novo case data were identified.
Still missing
- Documented maternity and paternity confirmation in an individual meeting HDGC criteria would be needed.
Sources
PS3 No variant-specific RNA study demonstrating an abnormal out-of-frame or in-frame transcript was identified, so PS3 is not applied. Details ▾Hide ▴
Rule
RNA assay demonstrating abnormal out-of-frame transcripts (Strong) or abnormal in-frame transcript (Moderate).
Evidence considered
- No qualifying RNA assay data were identified.
Still missing
- Variant-specific RNA analysis would be needed to assess abnormal transcript formation.
Sources
PM6 No assumed de novo observation meeting the CDH1 phenotype-specific requirements was identified. Details ▾Hide ▴
Rule
One or more patients meeting HDGC individual phenotype criteria without parental confirmation.
Evidence considered
- No de novo case data were identified.
Still missing
- A de novo observation without parental confirmation in an individual meeting HDGC criteria would be needed.
Sources
PP1 No segregation data were identified to show co-segregation with disease across informative meioses. Details ▾Hide ▴
Rule
Three or more informative meioses required for PP1 support, with higher strengths for additional meioses.
Evidence considered
- No qualifying segregation evidence was identified.
Still missing
- Family segregation data with counted informative meioses would be needed.
Sources
PP3 Available computational evidence does not support applying PP3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the retrieved evidence does not provide the three concordant splicing predictors required by the CDH1 specification for PP3. Details ▾Hide ▴
Rule
At least three in silico splicing predictors in agreement, or a well-characterized same-site splice comparator.
Evidence considered
- SpliceAI DS max 0.01 predicts no significant splice impact.
Still missing
- Additional accepted splice predictors in agreement would be needed to evaluate PP3 under the CDH1 rule.
Sources
BS2 No dataset of at least 3 or 10 clinically unaffected individuals without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer was identified for this variant, so BS2 is not applied. Details ▾Hide ▴
Rule
Observed in unaffected individuals without HDGC-related features, with supporting or strong thresholds based on count.
Evidence considered
- No qualifying unaffected-carrier series was identified.
Still missing
- Phenotyped unaffected carriers meeting the CDH1 BS2 rule would be needed.
Sources
BS3 No variant-specific functional RNA study demonstrating no impact on transcript composition was identified, so BS3 is not applied. Details ▾Hide ▴
Rule
Functional RNA studies demonstrating no impact on transcript composition.
Evidence considered
- No qualifying RNA study was identified.
Still missing
- Variant-specific RNA testing showing no transcript effect would be needed.
Sources
BS4 No family data showing lack of segregation with disease were identified. Details ▾Hide ▴
Rule
Per original ACMG/AMP guidelines with CDH1 cautions regarding phenocopies.
Evidence considered
- No qualifying non-segregation evidence was identified.
Still missing
- Family segregation data demonstrating non-segregation would be needed.
Sources
BP4 Available computational evidence does not justify BP4 under the CDH1 rule. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the retrieved evidence does not include the three concordant accepted splicing predictors required by the CDH1 specification. Details ▾Hide ▴
Rule
At least three in silico splicing predictors in agreement suggesting no splice impact.
Evidence considered
- SpliceAI DS max 0.01 predicts no significant splice impact.
Still missing
- Additional accepted splice predictors in agreement would be needed to evaluate BP4 under the CDH1 rule.
Sources
BP5 No alternate pathogenic or likely pathogenic variant in another HDGC-associated gene was identified to explain the phenotype, so BP5 is not applied. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
- No alternate molecular diagnosis was identified.
Still missing
- An alternate molecular explanation
- such as a pathogenic CTNNA1 variant
- would be needed.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 VCEPPS1 is not applicable for CDH1 under this specification. Details ▾Hide ▴
VCEP rule
Not applicable for CDH1.
Evidence considered
- CDH1 VCEP marks PS1 as not applicable.
Sources
PS4 N/APS4 is not applied because this variant meets BS1, and the CDH1 specification states that PS4 cannot be applied to variants that meet BS1 or BA1. Details ▾Hide ▴
Rule
PS4 cannot be applied to variants that meet BS1 or BA1.
Evidence considered
- Highest observed population frequency exceeds the BS1 threshold in gnomAD v2.1 and v4.1.
Sources
PM1 VCEPPM1 is not applicable for CDH1 under this specification. Details ▾Hide ▴
VCEP rule
Not applicable for CDH1.
Evidence considered
- CDH1 VCEP marks PM1 as not applicable.
Sources
PM3 VCEPPM3 is not applicable for CDH1 under this specification. Details ▾Hide ▴
VCEP rule
Not applicable for CDH1.
Evidence considered
- CDH1 VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is limited to stop-loss variants in CDH1, and this intronic variant is not a stop-loss variant. Details ▾Hide ▴
Rule
Only apply to stop-loss variants.
Evidence considered
- Variant is intronic c.1138-3C>T.
Sources
PM5 N/APM5 is not applied. In CDH1, PM5 is repurposed away from classic same-residue missense logic, and this intronic variant is not eligible for the truncating or canonical-splicing PM5 framework described for CDH1. Details ▾Hide ▴
Rule
CDH1 PM5_supporting applies to specified nonsense, frameshift, and site-specific canonical splicing scenarios.
Evidence considered
- PM5 candidate review marked classic PM5 search as ineligible for this variant.
Sources
cspec ↗pm5_candidates
PP2 VCEPPP2 is not applicable for CDH1 under this specification. Details ▾Hide ▴
VCEP rule
Not applicable for CDH1.
Evidence considered
- CDH1 VCEP marks PP2 as not applicable.
Sources
PP4 VCEPPP4 is not applicable for CDH1 under this specification. Details ▾Hide ▴
VCEP rule
Not applicable for CDH1.
Evidence considered
- CDH1 VCEP marks PP4 as not applicable.
Sources
PP5 VCEPPP5 is not used under this specification. Details ▾Hide ▴
VCEP rule
This criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.
Evidence considered
- CDH1 VCEP marks PP5 as not applicable.
Sources
BP1 VCEPBP1 is not applicable for CDH1 under this specification. Details ▾Hide ▴
VCEP rule
Not applicable for CDH1.
Evidence considered
- CDH1 VCEP marks BP1 as not applicable.
Sources
BP3 VCEPBP3 is not applicable for CDH1 under this specification. Details ▾Hide ▴
VCEP rule
Not applicable for CDH1.
Evidence considered
- CDH1 VCEP marks BP3 as not applicable.
Sources
Identifiers
- Gene
- CDH1
- Transcript
- NM_004360.5
- Coding (HGVS c.)
- NM_004360.5:c.1138-3C>T
- Protein (HGVS p.)
- NP_004351.1:p.?
- GRCh38
- chr16:68813310 C>T
- GRCh37
- chr16:68847213 C>T
- ClinVar
- 184346
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
152 / 1,613,954 alleles
AF 9.42e-05 · 3 homozygotes · FAF 0.00139
gnomAD v2.1
37 / 282,862 alleles
AF 0.000131 · 0 homozygotes · FAF 0.000815
By genetic ancestry
gnomAD v4.1
AF 9.4e-05 · 152 / 1,613,954 alleles · 3 hom · FAF 0.0014
| African/African American122 / 75,034 | 0.00163 hom |
| Remaining individuals15 / 62,506 | 0.00024 |
| Admixed American11 / 59,992 | 0.00018 |
| European (non-Finnish)4 / 1,179,876 | 3.4e-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 · 37 / 282,862 alleles · 0 hom · FAF 0.00082
| African/African American28 / 24,972 | 0.0011 |
| Admixed American8 / 35,440 | 0.00023 |
| Remaining individuals1 / 7,224 | 0.00014 |
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian.
Statements
gnomAD 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.
gnomAD 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 This intronic variant is at c.1138-3, which is not at or beyond the CDH1 BP7 intronic positions of +7 or -21, so BP7 is not applied. Details ▾Hide ▴
Rule
Synonymous and intronic variants at or beyond +7 to -21 locations.
Evidence considered
- Variant position is c.1138-3.
Sources
PP3 Available computational evidence does not support applying PP3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the retrieved evidence does not provide the three concordant splicing predictors required by the CDH1 specification for PP3. Details ▾Hide ▴
Rule
At least three in silico splicing predictors in agreement, or a well-characterized same-site splice comparator.
Evidence considered
- SpliceAI DS max 0.01 predicts no significant splice impact.
Still missing
- Additional accepted splice predictors in agreement would be needed to evaluate PP3 under the CDH1 rule.
Sources
BP4 Available computational evidence does not justify BP4 under the CDH1 rule. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the retrieved evidence does not include the three concordant accepted splicing predictors required by the CDH1 specification. Details ▾Hide ▴
Rule
At least three in silico splicing predictors in agreement suggesting no splice impact.
Evidence considered
- SpliceAI DS max 0.01 predicts no significant splice impact.
Still missing
- Additional accepted splice predictors in agreement would be needed to evaluate BP4 under the CDH1 rule.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
9 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
-
PMID 15322508 ↗International variation.Parkin DM · 2004No paper-specific finding is recorded.
-
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.
-
PMID 26123647 ↗Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate.Brito LA et al. · 2015No paper-specific finding is recorded.
-
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 27978560 ↗Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.Pearlman R et al. · 2017No paper-specific finding is recorded.
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PMID 28135145 ↗Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.Yurgelun MB et al. · 2017No 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.
-
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
152 / 1,613,954 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
7 Likely benign · 7 Benign
Open source ↗
COSMIC
Captured COSMIC 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/184346/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-68847213-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-68813310-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004360.5%3Ac.1138…
- OncoKB ↗www.oncokb.org/gene/CDH1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDH1+c.1138-3C%3ET
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= 9.41786e-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.
gnomAD 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.
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).