About CDH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDH1 c.1888C>G, p.(Leu630Val)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone
Population frequency exceeds the CDH1 BA1 threshold of 0.2%. The highest observed East Asian frequency is 0.48622% in gnomAD v2.1 (97/19950 alleles) and 0.56147% in gnomAD v4.1 (252/44882 alleles), both in subpopulations with more than 2000 alleles and more than 5 observed variant alleles.
BP6Supporting
BP6 · supporting
Expert panel Clingen Gastric Cancer Variant Curation Expert Panel classified as Benign.
Recorded classification: 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: BA1 stand-alone benign, BP6 supporting benign; combination = 1 stand-alone benign, which maps to 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
267 / 1,614,146 alleles
gnomAD v4.1: 267 / 1,614,146 alleles. Recorded AF 0.000165413. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000357057; MAF= 0.03571%, 101/282868 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00486216; MAF= 0.48622%, 97/19950 alleles, homozygotes = 0); grpmax FAF= 0.00412524.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000325768; MAF= 0.03258%, 6/18418 alleles, homozygotes = 0) and has highest observed frequency in the eas population (AF= 0.00224215; grpmax FAF95= 0.00061019).
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
12 reported laboratory submissions
7 Benign · 5 Likely benign.
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDH1 (E-cadherin), a tumor suppressor involved in cell adhesion, is altered by mutation or deletion in various cancer typess, most frequently in breas
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55733235, n = 5 times).
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: 2 met · 3 not met · 9 not assessed · 14 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.1888C>G (p.Leu630Val) variant has been reported in ClinVar with an expert-panel benign classification, alongside multiple benign and likely benign clinical laboratory submissions.
This variant is present in population databases at a frequency above the CDH1 benign stand-alone threshold, with the highest observed East Asian frequency of 0.48622% in gnomAD v2.1 and 0.56147% in gnomAD v4.1.
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.02; REVEL 0.345 and BayesDel -0.164621 are available as supporting context but are not used to apply CDH1 missense PP3 or BP4.
No criteria match.
Met · 2
BA1 Stand alonePopulation frequency exceeds the CDH1 BA1 threshold of 0.2%. The highest observed East Asian frequency is 0.48622% in gnomAD v2.1 (97/19950 alleles) and 0.56147% in gnomAD v4.1 (252/44882 alleles), both in subpopulations with more than 2000 alleles and more than 5 observed variant alleles. Details ▾Hide ▴
Rule
MAF cutoff of 0.2%.
Evidence considered
- gnomAD v2.1 East Asian AF 0.00486216.
- gnomAD v4.1 East Asian AF 0.00561472.
- gnomAD-Canada AF 0.000325768.
Sources
Not met · 3 · evaluated, threshold not reached
PS4 This variant is too common in population databases for PS4 under the CDH1 specification, and no qualifying HDGC-family count was identified. The highest observed East Asian frequency is 0.48622% in gnomAD v2.1 and 0.56147% in gnomAD v4.1, which is above the CDH1 BS1 and BA1 thresholds and argues against enrichment in affected individuals. Details ▾Hide ▴
Rule
PS4 cannot be applied to variants that meet BS1 or BA1.
Evidence considered
- CDH1 PS4 cannot be applied to variants that meet BS1 or BA1.
- gnomAD East Asian AF exceeds benign population thresholds.
Sources
PM2 Population frequency is well above the CDH1 PM2_Supporting threshold of no more than 1 in 100,000 alleles overall and no more than 1 in 50,000 alleles in a subpopulation with at least 2 observations. This variant is present at 101/282868 alleles in gnomAD v2.1, 267/1614146 alleles in gnomAD v4.1, and 97/19950 East Asian alleles in gnomAD v2.1. Details ▾Hide ▴
Rule
≤ One out of 100,000 alleles in gnomAD cohort; if present in ≥2 individuals within a subpopulation, must be present in ≤ One out of 50,000 alleles.
Evidence considered
- gnomAD v2.1 overall AF 0.000357057.
- gnomAD v4.1 overall AF 0.000165413.
- gnomAD v2.1 East Asian AF 0.00486216.
Sources
PP3 Available computational evidence does not support a splice-disrupting effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, and CDH1 PP3 is based on splicing evidence rather than protein-based missense prediction. REVEL 0.345 and BayesDel -0.164621 were available but are not used to apply CDH1 PP3 for missense variants. Details ▾Hide ▴
Rule
At least three in silico splicing predictors in agreement.
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.345.
- BayesDel score -0.164621.
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence in an individual meeting HDGC phenotype criteria was identified. Details ▾Hide ▴
PS3 No RNA study showing an abnormal out-of-frame or in-frame transcript for this variant was identified. Available evidence does not support applying PS3. Details ▾Hide ▴
Evidence considered
- The CDH1 VCEP restricts PS3 to splicing-defect evidence.
- SpliceAI predicts no significant splice impact for this variant.
Still missing
- Variant-specific RNA assay data were not identified.
Sources
PM6 No assumed de novo occurrence in an individual meeting HDGC phenotype criteria was identified. Details ▾Hide ▴
PP1 No segregation data were identified to show co-segregation with HDGC-related disease. Details ▾Hide ▴
BS1 Population frequency also exceeds the CDH1 BS1 threshold of 0.1%, but BA1 is already met at the higher benign population strength and is the population criterion applied here. Details ▾Hide ▴
Rule
MAF cutoff of 0.1%.
Evidence considered
- gnomAD v2.1 East Asian AF 0.00486216 exceeds 0.1%.
- gnomAD v4.1 East Asian AF 0.00561472 exceeds 0.1%.
Sources
BS2 No phenotyped series of at least 3 or 10 unaffected carriers without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer was identified, so BS2 cannot be assessed from the available evidence. Details ▾Hide ▴
BS4 No family data showing lack of segregation with disease were identified. Details ▾Hide ▴
BP2 No phase information showing this variant in cis or trans with a pathogenic variant, and no homozygous observation in gnomAD, were identified. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 homozygotes = 0.
- gnomAD v4.1 homozygotes = 0.
Still missing
- Confirmed phase or qualifying homozygous observation was not available.
Sources
BP5 No alternate pathogenic or likely pathogenic variant in another HDGC gene was identified to explain the phenotype instead of CDH1. Details ▾Hide ▴
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, canonical splice-site, initiation-codon, or deletion variant. Available CDH1 PVS1 guidance and the variant-level PVS1 assessment therefore do not support applying PVS1. Details ▾Hide ▴
Rule
Per modified CDH1 PVS1 decision tree.
Evidence considered
- CDH1 loss of function is an established disease mechanism in the CDH1 framework.
- NM_004360.5:c.1888C>G encodes p.(Leu630Val) and is not a default PVS1 variant class.
Sources
PS1 VCEPPS1 is not used in the CDH1 specification. Details ▾Hide ▴
PM1 VCEPPM1 is not used in the CDH1 specification. Details ▾Hide ▴
Evidence considered
- The CDH1 VCEP marks PM1 as not applicable.
- No hotspot evidence supporting PM1 was identified.
Sources
PM3 VCEPPM3 is not used in the CDH1 specification. Details ▾Hide ▴
PM4 N/AIn CDH1, PM4 is reserved for stop-loss variants. This variant is a missense change and does not meet that rule. Details ▾Hide ▴
Rule
Only apply to stop-loss variants.
Evidence considered
- The CDH1 VCEP applies PM4 only to stop-loss variants.
- NM_004360.5:c.1888C>G is p.(Leu630Val).
Sources
PM5 N/AIn the CDH1 specification, PM5 is repurposed for truncating or specific splice-related logic rather than classic same-residue missense comparison. The PM5 review artifact found that classic same-residue PM5 searching is not eligible for this missense variant. Details ▾Hide ▴
Rule
PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant.
Evidence considered
- The CDH1 VCEP repurposes PM5 for PTC or truncating logic.
- The PM5 candidate review marked this variant not applicable for classic PM5 search.
Sources
cspec ↗pm5_candidates
PP2 VCEPPP2 is not used in the CDH1 specification. Details ▾Hide ▴
PP4 VCEPPP4 is not used in the CDH1 specification. Details ▾Hide ▴
PP5 VCEPPP5 is not used in the CDH1 specification. Details ▾Hide ▴
BS3 N/AIn the CDH1 specification, BS3 is limited to synonymous, intronic, or non-coding variants with RNA evidence showing no impact on transcript composition. This variant is missense, so BS3 is not applicable. Details ▾Hide ▴
Rule
Functional RNA studies demonstrating no impact on transcript composition.
Evidence considered
- The CDH1 VCEP restricts BS3 to synonymous
- intronic
- or non-coding variants.
- This variant is p.(Leu630Val).
Sources
BP1 VCEPBP1 is not used in the CDH1 specification. Details ▾Hide ▴
BP3 VCEPBP3 is not used in the CDH1 specification. Details ▾Hide ▴
BP4 N/ABP4 is not applied to missense variants in the CDH1 specification. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, and protein-based missense predictors such as REVEL 0.345 and BayesDel -0.164621 are not used to apply CDH1 BP4. Details ▾Hide ▴
Rule
Do not use protein based computational prediction models and BP4 is not applicable for missense variants.
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.345.
- BayesDel score -0.164621.
Sources
BP7 N/ABP7 is restricted to synonymous and qualifying intronic variants. This variant is a missense change and does not meet BP7. Details ▾Hide ▴
Rule
Synonymous and intronic variants at or beyond +7 to -21 locations.
Evidence considered
- NM_004360.5:c.1888C>G is p.(Leu630Val).
- BP7 in CDH1 applies to synonymous and certain intronic variants.
Sources
Identifiers
- Gene
- CDH1
- Transcript
- NM_004360.5
- Coding (HGVS c.)
- NM_004360.5:c.1888C>G
- Protein (HGVS p.)
- NP_004351.1:p.(Leu630Val)
- GRCh38
- chr16:68822177 C>G
- GRCh37
- chr16:68856080 C>G
- ClinVar
- 133846
- COSMIC
- COSV55733235
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
267 / 1,614,146 alleles
AF 0.000165 · 0 homozygotes · FAF 0.00505
gnomAD v2.1
101 / 282,868 alleles
AF 0.000357 · 0 homozygotes · FAF 0.00413
gnomAD-Canada v1.0
6 / 18,418 alleles
AF 0.000326 · 0 homozygotes · FAF 0.00061
By genetic ancestry
gnomAD v4.1
AF 0.00017 · 267 / 1,614,146 alleles · 0 hom · FAF 0.005
| East Asian252 / 44,882 | 0.0056 |
| Remaining individuals7 / 62,510 | 0.00011 |
| South Asian8 / 91,080 | 8.8e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 0.00036 · 101 / 282,868 alleles · 0 hom · FAF 0.0041
| East Asian97 / 19,950 | 0.0049 |
| Remaining individuals3 / 7,226 | 0.00042 |
| South Asian1 / 30,616 | 3.3e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish).
gnomAD-Canada
AF 0.00033 · 6 / 18,418 alleles · 0 hom · FAF 0.00061
| eas3 / 1,338 | 0.0022 |
| sas2 / 1,362 | 0.0015 |
| oth1 / 1,138 | 0.00088 |
0 alternate alleles recorded in 6 other groups: afr, amr, asj, fin, mid, nfe.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000165413; MAF= 0.01654%, 267/1614146 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00561472; MAF= 0.56147%, 252/44882 alleles, homozygotes = 0); grpmax FAF= 0.00504519.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000357057; MAF= 0.03571%, 101/282868 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00486216; MAF= 0.48622%, 97/19950 alleles, homozygotes = 0); grpmax FAF= 0.00412524.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000325768; MAF= 0.03258%, 6/18418 alleles, homozygotes = 0) and has highest observed frequency in the eas population (AF= 0.00224215; grpmax FAF95= 0.00061019).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.345
- BayesDel
- -0.165
How the predictions were used
PP3 Available computational evidence does not support a splice-disrupting effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, and CDH1 PP3 is based on splicing evidence rather than protein-based missense prediction. REVEL 0.345 and BayesDel -0.164621 were available but are not used to apply CDH1 PP3 for missense variants. Details ▾Hide ▴
Rule
At least three in silico splicing predictors in agreement.
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.345.
- BayesDel score -0.164621.
Sources
BP4 N/ABP4 is not applied to missense variants in the CDH1 specification. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, and protein-based missense predictors such as REVEL 0.345 and BayesDel -0.164621 are not used to apply CDH1 BP4. Details ▾Hide ▴
Rule
Do not use protein based computational prediction models and BP4 is not applicable for missense variants.
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.345.
- BayesDel score -0.164621.
Sources
BP7 N/ABP7 is restricted to synonymous and qualifying intronic variants. This variant is a missense change and does not meet BP7. Details ▾Hide ▴
Rule
Synonymous and intronic variants at or beyond +7 to -21 locations.
Evidence considered
- NM_004360.5:c.1888C>G is p.(Leu630Val).
- BP7 in CDH1 applies to synonymous and certain intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.345. BayesDel score = -0.164621.
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
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PMID 23431106 ↗Novel CDH1 germline mutations identified in Chinese gastric cancer patients.Chen QH et al. · 2013No paper-specific finding is recorded.
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No 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 26086041 ↗Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry.Yurgelun MB et al. · 2015No 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 26757417 ↗Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing.Ng PS et al. · 2016No paper-specific finding is recorded.
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PMID 32566746 ↗Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome.No paper-specific finding is recorded.
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PMID 12692171 ↗American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.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
267 / 1,614,146 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
7 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/133846/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-68856080-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-68822177-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-68822177-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004360.5%3Ac.1888…
- OncoKB ↗www.oncokb.org/gene/CDH1/L630V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121139083
- 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= 0.000165413; MAF= 0.01654%, 267/1614146 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00561472; MAF= 0.56147%, 252/44882 alleles, homozygotes = 0); grpmax FAF= 0.00504519.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000357057; MAF= 0.03571%, 101/282868 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00486216; MAF= 0.48622%, 97/19950 alleles, homozygotes = 0); grpmax FAF= 0.00412524.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000325768; MAF= 0.03258%, 6/18418 alleles, homozygotes = 0) and has highest observed frequency in the eas population (AF= 0.00224215; grpmax FAF95= 0.00061019).
ClinVar
This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (5 clinical laboratories) and as Benign by Clingen Gastric Cancer Variant Curation Expert Panel (expert panel). (ClinVarID = 133846)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.345. BayesDel score = -0.164621.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDH1 (E-cadherin), a tumor suppressor involved in cell adhesion, is altered by mutation or deletion in various cancer typess, most frequently in breas
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55733235, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.