About CDH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDH1 c.1266A>G, p.(Gln422=)
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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP7Supporting
BP7 · supporting
NM_004360.5:c.1266A>G is a synonymous variant (p.Gln422=) in exon 9. Under CDH1 CSPEC v3.1, BP7 applies to synonymous variants without requiring a conservation prediction. SpliceAI predicts no splice impact (max delta = 0.00), and the variant is located 54 nucleotides upstream of the exon 9 donor splice site, well outside the splice consensus region.
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: BP7 supporting; combination = 1 supporting benign, 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
15 / 1,614,208 alleles
gnomAD v4.1: 15 / 1,614,208 alleles. Recorded AF 9.29248e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.1929e-05; MAF= 0.00119%, 3/251488 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
8 reported laboratory submissions
7 Likely benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55734749, n = 1 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, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 16 not met · 0 not assessed · 9 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.1266A>G (p.Gln422=) is a synonymous variant in CDH1 exon 9.
SpliceAI predicts no impact on splicing (max delta score = 0.00).
BP7 (supporting) is applied per CDH1 CSPEC v3.1: synonymous variant without requirement for conservation prediction.
The variant is present in gnomAD at very low frequency: 3/251,488 alleles in v2.1 (0.00119%) and 15/1,614,208 alleles in v4.1 (0.00093%), with no homozygotes.
In ClinVar, this variant is classified as Likely benign by 7 clinical laboratories and as Benign by 1 clinical laboratory (ClinVar Variation ID: 185874, 1-star review status).
No pathogenic criteria are met. Only BP7 (supporting benign) is applicable. With a single supporting benign criterion, the formal ACMG/AMP classification is Variant of Uncertain Significance; however, the clinical consensus from 8 diagnostic laboratories supports a Likely benign interpretation for this synonymous variant with no predicted splice impact.
No criteria match.
Met · 1
BP7 SupportingNM_004360.5:c.1266A>G is a synonymous variant (p.Gln422=) in exon 9. Under CDH1 CSPEC v3.1, BP7 applies to synonymous variants without requiring a conservation prediction. SpliceAI predicts no splice impact (max delta = 0.00), and the variant is located 54 nucleotides upstream of the exon 9 donor splice site, well outside the splice consensus region. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.Gln422=
- CDH1 CSPEC BP7 does not require conservation prediction
- SpliceAI delta = 0.00
- variant is 54 bp from nearest splice donor.
Sources
Not met · 16 · evaluated, threshold not reached
PVS1 NM_004360.5:c.1266A>G is a synonymous variant (p.Gln422=) and does not meet the PVS1 null-variant criteria under the CDH1 CSPEC v3.1 decision tree, which covers nonsense, frameshift, canonical ±1,2 splice site, initiation codon, and exon deletion variants. Details ▾Hide ▴
Evidence considered
- Synonymous substitution
- not a null variant
- pvs1_variant_assessment confirms variant_bucket='other' and applies_generic_pvs1_framework=false.
Sources
cspec ↗pvs1_variant_assessment
PS2 No de novo observations with confirmed maternity and paternity meeting HDGC individual phenotype criteria are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports found in ClinVar
- literature
- or case materials.
Still missing
- No family or de novo data available.
PS3 Under CDH1 CSPEC v3.1, PS3 is restricted to RNA assays demonstrating abnormal transcripts. No RNA studies have been performed for this variant. SpliceAI predicts no splice impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00
- no functional RNA studies available.
Still missing
- No RNA functional studies performed.
Sources
PS4 No families meeting HDGC criteria have been reported for this variant. The variant is a synonymous change classified as likely benign/benign in ClinVar by 8 clinical laboratories, inconsistent with a pathogenic enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- No HDGC families reported
- variant classified as likely benign (7 labs) / benign (1 lab) in ClinVar.
Still missing
- No case-control or family data available.
Sources
PM2 The variant is present in gnomAD at low frequency. In v2.1, it is observed in 3/251,488 alleles (0.00119%, ~1.19/100,000), which slightly exceeds the CDH1 CSPEC PM2_Supporting threshold of ≤1/100,000 alleles. In v4.1, it is observed in 15/1,614,208 alleles (0.00093%), but is present in 2/6,062 Middle Eastern alleles (0.033%), exceeding the subpopulation threshold of ≤1/50,000 when present in ≥2 individuals. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 3/251
- 488 alleles (AF=0.00119%)
- gnomAD v4.1: 15/1
- 614
- 208 alleles (AF=0.00093%)
- Middle Eastern subpop: 2/6
- 062 (AF=0.033%).
Sources
PM6 No assumed de novo observations (without parental confirmation) meeting HDGC individual phenotype criteria are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo or assumed de novo reports found.
Still missing
- No de novo data available.
PP1 No cosegregation data with informative meioses are available for this variant. Details ▾Hide ▴
Evidence considered
- No family cosegregation studies reported.
Still missing
- No cosegregation data available.
PP3 Under CDH1 CSPEC v3.1, PP3 requires at least three in silico splicing predictors in agreement. Only SpliceAI data is available (delta = 0.00, no splice impact). Without ≥3 independent splicing predictors, PP3 cannot be applied. Additionally, the CSPEC instructs not to use protein-based computational prediction models for missense variants, and this synonymous variant has no predicted splice impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no other splicing predictors available in the evidence packet.
Still missing
- Only 1 of ≥3 required splicing predictors available.
Sources
BA1 The CDH1 CSPEC BA1 threshold is MAF >0.2%. The highest observed frequency in gnomAD is 0.033% (Middle Eastern, gnomAD v4.1), well below the 0.2% cutoff. Additionally, the CSPEC requires ≥2,000 alleles and ≥5 variant alleles in the subpopulation; no subpopulation meets both criteria. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpop AF = 0.033% (Middle Eastern
- 2/6
- 062)
- well below 0.2% BA1 threshold.
Sources
BS1 The CDH1 CSPEC BS1 threshold is MAF >0.1%. The highest observed frequency in gnomAD is 0.033% (Middle Eastern, v4.1), below the cutoff. Additionally, the CSPEC requires ≥2,000 alleles and ≥5 variant alleles in the subpopulation; no subpopulation meets both criteria. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpop AF = 0.033%
- below 0.1% BS1 threshold
- subpop criteria not met.
Sources
BS2 BS2 requires ≥10 individuals without gastric cancer, DGC, SRC tumors, or LBC and whose families do not suggest HDGC. While the variant is observed in 18 individuals across gnomAD (3 in v2.1, 15 in v4.1), phenotype data confirming absence of HDGC-related cancers are not available for these population cohorts. Details ▾Hide ▴
Evidence considered
- gnomAD: 18 total carriers across v2.1 and v4.1
- no phenotype data confirming absence of HDGC-related cancers available.
Still missing
- Individual-level phenotype confirmation not available from gnomAD.
Sources
BS3 Under CDH1 CSPEC v3.1, BS3 requires functional RNA studies demonstrating no impact on transcript composition. This synonymous variant has SpliceAI delta = 0.00 (predicting no splice impact), but no experimental RNA studies have been performed. In silico prediction alone does not satisfy the functional data requirement. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00
- no RNA functional studies performed.
Still missing
- No RNA functional studies performed
- only in silico prediction available.
Sources
BS4 No segregation data are available to assess lack of segregation in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family data.
BP2 No evidence of the variant in trans with a known pathogenic variant or in a homozygous state in an individual without HDGC-related cancer history. The variant has 0 homozygotes in gnomAD. Details ▾Hide ▴
Evidence considered
- gnomAD: 0 homozygotes
- no cis/trans phase data available.
Still missing
- No phase data or homozygous observations.
Sources
BP4 Under CDH1 CSPEC v3.1, BP4 requires at least three in silico splicing predictors in agreement. Only SpliceAI data is available (delta = 0.00, predicting no splice impact). Without ≥3 independent predictors, BP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- only 1 of ≥3 required splicing predictors available.
Still missing
- Only 1 splicing predictor available
- need ≥3 (e.g.
- MaxEntScan
- SSF
- GeneSplicer) per CSPEC.
Sources
BP5 BP5 applies when a pathogenic/likely pathogenic variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1). No such finding has been reported for individuals carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis for disease identified.
Still missing
- No data on alternate gene findings.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 VCEPPS1 is not applicable under the CDH1 CSPEC v3.1. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is not applicable under the CDH1 CSPEC v3.1. Details ▾Hide ▴
Sources
PM5 N/AUnder CDH1 CSPEC v3.1, PM5_Supporting is applicable only to nonsense and frameshift variants predicted to undergo NMD or located upstream of the last known pathogenic truncating variant. This is a synonymous variant. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- PM5 repurposed for PTC/truncating logic per CSPEC
- pm5_candidates confirms eligible_for_classic_pm5_search=false.
Sources
cspec ↗pm5_candidates
PP2 VCEPPP2 is not applicable under the CDH1 CSPEC v3.1. Details ▾Hide ▴
Sources
PP4 VCEPPP4 is not applicable under the CDH1 CSPEC v3.1. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is not for use under the CDH1 CSPEC v3.1 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No ClinVar 3-star expert panel submission exists to trigger the global PP5 override. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable under the CDH1 CSPEC v3.1. Details ▾Hide ▴
Sources
BP6 VCEPBP6 is not for use under the CDH1 CSPEC v3.1 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No ClinVar 3-star expert panel benign submission exists to trigger the global BP6 override. Details ▾Hide ▴
PS5 N/APS5 is not defined in the CDH1 CSPEC v3.1 criteria set. Details ▾Hide ▴
Sources
Identifiers
- Gene
- CDH1
- Transcript
- NM_004360.5
- Coding (HGVS c.)
- NM_004360.5:c.1266A>G
- Protein (HGVS p.)
- NP_004351.1:p.(Gln422=)
- GRCh38
- chr16:68813441 A>G
- GRCh37
- chr16:68847344 A>G
- ClinVar
- 185874
- COSMIC
- COSV55734749
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
15 / 1,614,208 alleles
AF 9.29e-06 · 0 homozygotes · FAF 5.82e-05
gnomAD v2.1
3 / 251,488 alleles
AF 1.19e-05 · 0 homozygotes · FAF 2.92e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 9.3e-06 · 15 / 1,614,208 alleles · 0 hom · FAF 5.8e-05
| Middle Eastern2 / 6,062 | 0.00033 |
| South Asian3 / 91,078 | 3.3e-05 |
| European (non-Finnish)10 / 1,180,024 | 8.5e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.2e-05 · 3 / 251,488 alleles · 0 hom · FAF 2.9e-06
| South Asian1 / 30,616 | 3.3e-05 |
| European (non-Finnish)2 / 113,764 | 1.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.29248e-06; MAF= 0.00093%, 15/1614208 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329924; MAF= 0.03299%, 2/6062 alleles, homozygotes = 0); grpmax FAF= 5.818e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.1929e-05; MAF= 0.00119%, 3/251488 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingNM_004360.5:c.1266A>G is a synonymous variant (p.Gln422=) in exon 9. Under CDH1 CSPEC v3.1, BP7 applies to synonymous variants without requiring a conservation prediction. SpliceAI predicts no splice impact (max delta = 0.00), and the variant is located 54 nucleotides upstream of the exon 9 donor splice site, well outside the splice consensus region. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.Gln422=
- CDH1 CSPEC BP7 does not require conservation prediction
- SpliceAI delta = 0.00
- variant is 54 bp from nearest splice donor.
Sources
PP3 Under CDH1 CSPEC v3.1, PP3 requires at least three in silico splicing predictors in agreement. Only SpliceAI data is available (delta = 0.00, no splice impact). Without ≥3 independent splicing predictors, PP3 cannot be applied. Additionally, the CSPEC instructs not to use protein-based computational prediction models for missense variants, and this synonymous variant has no predicted splice impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no other splicing predictors available in the evidence packet.
Still missing
- Only 1 of ≥3 required splicing predictors available.
Sources
BP4 Under CDH1 CSPEC v3.1, BP4 requires at least three in silico splicing predictors in agreement. Only SpliceAI data is available (delta = 0.00, predicting no splice impact). Without ≥3 independent predictors, BP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- only 1 of ≥3 required splicing predictors available.
Still missing
- Only 1 splicing predictor available
- need ≥3 (e.g.
- MaxEntScan
- SSF
- GeneSplicer) per CSPEC.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 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 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.ACMG/AMP 2015 standards and guidelines for the interpretation of sequence variants. General framework paper; does not mention NM_004360.5:c.1266A>G or any CDH1-specific variant.Does not name this variant
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Sherloc: a standardized DNA variant scoring system for pathogenicity assessments in Mendelian disorders. Describes a rules-based classification framework; does not mention NM_004360.5:c.1266A>G or any CDH1-specific variant.Does not name this variant
-
PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.Robson ME et al. · 2010ASCO policy statement on genetic and genomic testing for cancer susceptibility. General policy document; does not mention NM_004360.5:c.1266A>G.Does not name this variant
-
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. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. General guideline; does not mention NM_004360.5:c.1266A>G.Does not name this variant
-
PMID 26324357 ↗American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.Robson ME et al. · 2015ASCO policy statement update on genetic and genomic testing for cancer susceptibility. General policy document; does not mention NM_004360.5:c.1266A>G.Does not name this variant
-
PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ summary on Genetics of Breast and Gynecologic Cancers. General reference; does not mention NM_004360.5:c.1266A>G.Does not name this variant
-
PMID 29939840 ↗Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.ASCO guideline on management of advanced HER2+ breast cancer with brain metastases. Not relevant to CDH1 or this variant.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Classification framework paper cited by Invitae submission; does not mention NM_004360.5:c.1266A>G.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
15 / 1,614,208 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
7 Likely benign · 1 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/185874/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-68847344-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-68813441-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-68813441-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004360.5%3Ac.1266…
- OncoKB ↗www.oncokb.org/gene/CDH1/Q422=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121133468
- 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= 9.29248e-06; MAF= 0.00093%, 15/1614208 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329924; MAF= 0.03299%, 2/6062 alleles, homozygotes = 0); grpmax FAF= 5.818e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.1929e-05; MAF= 0.00119%, 3/251488 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 185874)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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 previously been reported in somatic cancers (COSMIC; COSV55734749, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.