About CDH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDH1 c.2077G>A, p.(Gly693Ser)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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. 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: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1 v3.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.
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
40 / 1,613,890 alleles
gnomAD v4.1: 40 / 1,613,890 alleles. Recorded AF 2.47848e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.24373e-05; MAF= 0.00424%, 12/282770 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.74257e-05; MAF= 0.00774%, 10/129156 alleles, homozygotes = 0); grpmax FAF= 4.736e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.120 maximum delta
Recorded SpliceAI maximum delta score: 0.120. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
1 Benign · 1 Likely benign · 1 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
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
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, with the data and sources behind each one.
26 criteria with recorded statuses: 0 met · 15 not met · 0 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
NM_004360.5:c.2077G>A (p.Gly693Ser) is a missense variant in CDH1 exon 13. Under the ClinGen CDH1 Expert Panel Specifications Version 3.1, no pathogenic or benign criteria are met. PVS1 is not applicable to missense variants. PM2 is not met because the variant exceeds the VCEP threshold of ≤1 per 100,000 alleles (gnomAD v2.1: ~4.2/100,000; v4.1: ~2.5/100,000). Population frequency is insufficient for BA1 (cutoff 0.2%) or BS1 (cutoff 0.1%). SpliceAI predicts no significant splicing impact (max delta 0.12), and PP3/BP4 are restricted to splicing predictors under the VCEP. No de novo, segregation, case-control, or functional data for this variant were identified among the four reviewed publications or ClinVar submissions. Multiple criteria are designated as Not Applicable by the CDH1 VCEP (PS1, PM1, PP2, PP4, BP1, PP5, BP6). The variant is classified as a Variant of Uncertain Significance.
No criteria match.
Not met · 15 · evaluated, threshold not reached
PVS1 PVS1 is not applicable to missense variants. NM_004360.5:c.2077G>A is a missense substitution (p.Gly693Ser) in exon 13 and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 application under the CDH1 VCEP modified decision tree. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant
- excluded from PVS1 by CDH1 VCEP modified decision tree.
Sources
pvs1_variant_assessmentpvs1_gene_context
PS2 No de novo observation of NM_004360.5:c.2077G>A with parental confirmation meeting HDGC individual phenotype criteria has been identified in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo reports identified for this variant.
Still missing
- No de novo data available for this variant.
PS3 Under the CDH1 VCEP, PS3 can only be applied to demonstrate splicing defects via RNA assays. NM_004360.5:c.2077G>A is a missense variant with no evidence of splicing impact (SpliceAI max delta score 0.12). No RNA assay or functional data demonstrating abnormal transcripts have been reported for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.12 indicates no significant splice impact
- no RNA assay data available.
Still missing
- No functional or RNA splicing studies available for this variant.
Sources
PS4 No families meeting HDGC criteria and harboring NM_004360.5:c.2077G>A have been identified in the reviewed literature. The variant is present in gnomAD at low frequency but no case-control or family-based association data exist. Details ▾Hide ▴
Evidence considered
- No HDGC families reported with this variant
- variant is not enriched in affected individuals.
Still missing
- No case-control or family aggregation data for this variant.
Sources
PM2 Under the CDH1 VCEP, PM2_Supporting requires ≤1 allele per 100,000 in gnomAD. This variant is observed at 12/282,770 alleles (AF=0.0042%, ~4.2 per 100,000) in gnomAD v2.1 and 40/1,613,890 alleles (AF=0.0025%, ~2.5 per 100,000) in gnomAD v4.1, both exceeding the VCEP PM2_Supporting threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 12/282
- 770 (~4.2/100
- 000)
- v4.1: 40/1
- 613
- 890 (~2.5/100
- both exceed VCEP threshold of ≤1/100
- 000.
Sources
PM6 No patients with NM_004360.5:c.2077G>A meeting HDGC individual phenotype criteria (without parental confirmation) have been identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- No assumed de novo reports identified for this variant.
Still missing
- No de novo or assumed de novo data for this variant.
PP1 No co-segregation data across informative meioses in families harboring NM_004360.5:c.2077G>A have been identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- No segregation data available for this variant.
Still missing
- No family-based segregation data.
PP3 Under the CDH1 VCEP, PP3 is restricted to splicing predictions only (at least three in silico splicing predictors in agreement) and protein-based models are not to be used for missense variants. SpliceAI shows no significant splice impact (max delta 0.12). No additional splicing predictors are available to demonstrate a deleterious splicing effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.12: no significant splice impact
- REVEL 0.042 and BayesDel -0.7031 indicate benign computational profile but are not applicable under VCEP PP3 rules for missense variants.
Sources
BA1 The CDH1 VCEP BA1 allele frequency threshold is 0.2%. This variant has a global MAF of 0.0042% in gnomAD v2.1 and 0.0025% in gnomAD v4.1, both well below the BA1 cutoff. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0.0042%
- v4.1: 0.0025%
- both below VCEP BA1 cutoff of 0.2%.
Sources
BS1 The CDH1 VCEP BS1 allele frequency threshold is 0.1%. This variant has a global MAF of 0.0042% in gnomAD v2.1 and 0.0025% in gnomAD v4.1, both well below the BS1 cutoff. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0.0042%
- v4.1: 0.0025%
- both below VCEP BS1 cutoff of 0.1%.
Sources
BS2 The CDH1 VCEP requires observation in ≥3 individuals without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer whose families do not suggest HDGC. While this variant is present in gnomAD (12 heterozygotes in v2.1, 40 in v4.1), the phenotype of these carriers is unknown, precluding BS2 application. Details ▾Hide ▴
Evidence considered
- Variant present in gnomAD but phenotype of carriers unknown
- insufficient data to confirm absence of HDGC-related phenotypes.
Still missing
- Phenotype data for gnomAD carriers not available
- cannot confirm they meet BS2 criteria.
Sources
BS4 No segregation data are available for NM_004360.5:c.2077G>A to evaluate lack of segregation in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation studies available.
BP2 No homozygotes for NM_004360.5:c.2077G>A are observed in gnomAD (0 homozygotes in both v2.1 and v4.1), and no data on observation in trans with a known pathogenic variant are available. Details ▾Hide ▴
Evidence considered
- No homozygotes in gnomAD
- no trans data available.
Still missing
- No phase-confirmed trans observations with a pathogenic CDH1 variant.
Sources
BP5 The CDH1 VCEP applies BP5 when a pathogenic/likely pathogenic variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1). No such data are available for this case. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis for HDGC identified.
Still missing
- No data on CTNNA1 variant status.
PS5 ClinVar reports this variant as Benign (1 clinical laboratory), Likely benign (1 clinical laboratory), and Uncertain significance (1 clinical laboratory). No reputable source has reported this variant as pathogenic; the ClinVar consensus does not support PS5 application. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Benign/Likely benign/VUS
- no expert panel classification
- no reputable source reporting as pathogenic.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 VCEPPS1 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Details ▾Hide ▴
Sources
PM1 VCEPPM1 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1. Details ▾Hide ▴
Sources
PM5 N/AUnder the CDH1 VCEP, PM5 is repurposed to apply only to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant (c.2506G>T). NM_004360.5:c.2077G>A is a missense variant and does not meet these criteria. Details ▾Hide ▴
Evidence considered
- Missense variant
- CDH1 VCEP restricts PM5 to nonsense/frameshift variants upstream of c.2506G>T.
Sources
cspec ↗pm5_candidates
PP2 VCEPPP2 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1. Details ▾Hide ▴
Sources
PP4 VCEPPP4 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BS3 N/AUnder the CDH1 VCEP, BS3 can only be used to demonstrate lack of splicing and can only be applied to synonymous, intronic, or non-coding variants. NM_004360.5:c.2077G>A is a missense variant, which is excluded from BS3 application. Details ▾Hide ▴
Evidence considered
- BS3 restricted to synonymous/intronic/non-coding variants under CDH1 VCEP
- missense variant excluded.
Sources
BP1 VCEPBP1 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1. Details ▾Hide ▴
Sources
BP4 N/AUnder the CDH1 VCEP, BP4 is restricted to splicing predictions only (at least three in silico splicing predictors in agreement) and is not applicable for missense variants. Details ▾Hide ▴
Evidence considered
- BP4 restricted to splicing predictors only
- missense variant excluded per CDH1 VCEP.
Sources
BP6 VCEPBP6 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BP7 N/AUnder the CDH1 VCEP, BP7 applies only to synonymous and intronic variants at or beyond +7 to -21 locations. NM_004360.5:c.2077G>A is a missense variant and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous and intronic variants per CDH1 VCEP.
Sources
Identifiers
- Gene
- CDH1
- Transcript
- NM_004360.5
- Coding (HGVS c.)
- NM_004360.5:c.2077G>A
- Protein (HGVS p.)
- NP_004351.1:p.(Gly693Ser)
- GRCh38
- chr16:68823539 G>A
- GRCh37
- chr16:68857442 G>A
- ClinVar
- 41785
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in CDH1
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
40 / 1,613,890 alleles
AF 2.48e-05 · 0 homozygotes · FAF 1.99e-05
gnomAD v2.1
12 / 282,770 alleles
AF 4.24e-05 · 0 homozygotes · FAF 4.74e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-05 · 40 / 1,613,890 alleles · 0 hom · FAF 2e-05
| European (non-Finnish)33 / 1,180,002 | 2.8e-05 |
| African/African American2 / 74,880 | 2.7e-05 |
| East Asian1 / 44,898 | 2.2e-05 |
| South Asian2 / 91,070 | 2.2e-05 |
| Remaining individuals1 / 62,488 | 1.6e-05 |
| European (Finnish)1 / 63,976 | 1.6e-05 |
0 alternate alleles recorded in 4 other groups: Admixed American, Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 4.2e-05 · 12 / 282,770 alleles · 0 hom · FAF 4.7e-05
| European (non-Finnish)10 / 129,156 | 7.7e-05 |
| African/African American1 / 24,954 | 4e-05 |
| South Asian1 / 30,616 | 3.3e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47848e-05; MAF= 0.00248%, 40/1613890 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.79661e-05; MAF= 0.00280%, 33/1180002 alleles, homozygotes = 0); grpmax FAF= 1.994e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.24373e-05; MAF= 0.00424%, 12/282770 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.74257e-05; MAF= 0.00774%, 10/129156 alleles, homozygotes = 0); grpmax FAF= 4.736e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.042
- BayesDel
- -0.703
How the predictions were used
PP3 Under the CDH1 VCEP, PP3 is restricted to splicing predictions only (at least three in silico splicing predictors in agreement) and protein-based models are not to be used for missense variants. SpliceAI shows no significant splice impact (max delta 0.12). No additional splicing predictors are available to demonstrate a deleterious splicing effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.12: no significant splice impact
- REVEL 0.042 and BayesDel -0.7031 indicate benign computational profile but are not applicable under VCEP PP3 rules for missense variants.
Sources
BP4 N/AUnder the CDH1 VCEP, BP4 is restricted to splicing predictions only (at least three in silico splicing predictors in agreement) and is not applicable for missense variants. Details ▾Hide ▴
Evidence considered
- BP4 restricted to splicing predictors only
- missense variant excluded per CDH1 VCEP.
Sources
BP7 N/AUnder the CDH1 VCEP, BP7 applies only to synonymous and intronic variants at or beyond +7 to -21 locations. NM_004360.5:c.2077G>A is a missense variant and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous and intronic variants per CDH1 VCEP.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.042. BayesDel score = -0.7031.
4 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 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Describes a standardized rules-based scoring system for DNA variant classification in Mendelian disorders. NM_004360.5:c.2077G>A (p.Gly693Ser) was not identified in this paper.Does not name this variant
-
PMID 22703879 ↗Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.Johnston JJ et al. · 2012Screens 572 individuals via exome sequencing for secondary variants in 37 cancer-susceptibility genes including CDH1. The only CDH1 variant discussed is c.892G>A (p.Ala298Thr) in two unrelated probands. NM_004360.5:c.2077G>A (p.Gly693Ser) was not identified in this paper.Does not name this variant
Quoted passage
One example of a class 3 variant for which the literature review and analysis of our data led to the downgrading of its pathogenicity is a variant in CDH1 (MIM 192090), c.892G>A (RefSeq NM_004360.3) (p.Ala298Thr), in two unrelated ClinSeq probands with negative family histories.
Results, CDH1 discussion para; Figure 4D
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015Practice guideline from ACMG and NSGC providing referral indications for cancer predisposition assessment. CDH1 is discussed in the context of hereditary diffuse gastric cancer referral criteria. NM_004360.5:c.2077G>A (p.Gly693Ser) was not mentioned.Does not name this variant
-
PMID 33471991 ↗Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.Breast Cancer Association Consortium et al. · 2021Association analysis of breast cancer risk genes in more than 113,000 women. NM_004360.5:c.2077G>A (p.Gly693Ser) was not identified in available abstract or metadata.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
40 / 1,613,890 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.120
Open source ↗
ClinVar
1 Benign · 1 Likely benign · 1 Uncertain significance
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/41785/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-68857442-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-68823539-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-68823539-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004360.5%3Ac.2077…
- OncoKB ↗www.oncokb.org/gene/CDH1/G693S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDH1+c.2077G%3EA
- 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= 2.47848e-05; MAF= 0.00248%, 40/1613890 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.79661e-05; MAF= 0.00280%, 33/1180002 alleles, homozygotes = 0); grpmax FAF= 1.994e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.24373e-05; MAF= 0.00424%, 12/282770 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.74257e-05; MAF= 0.00774%, 10/129156 alleles, homozygotes = 0); grpmax FAF= 4.736e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 41785)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.042. BayesDel score = -0.7031.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.