Classification rationale

BS1BP2BP6 Likely Benign

CDH1 c.1138-3C>T

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.¹ 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 v2.1.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.³

BS1 + BP2 + BP6 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 spliceai ↗

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.

Gene diagram · NM_004360.5 · variants mapped to exon structure

CDH1 NM_004360.5

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BS1 strong review Benign

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).

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.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BP2 supporting review Benign

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.

gnomAD v4.1 homozygotes = 3.

cspec ↗gnomad_v4 ↗

BP6 supporting review Benign

Expert panel Clingen Gastric Cancer Variant Curation Expert Panel classified as Likely benign.

CDH1 VCEP marks BP6 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

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.

PS2 No confirmed de novo observation meeting the CDH1 phenotype-specific requirements was identified.

PS3 No variant-specific RNA study demonstrating an abnormal out-of-frame or in-frame transcript was identified, so PS3 is not applied.

PM2 Population frequency is above the CDH1 PM2 threshold.

PM6 No assumed de novo observation meeting the CDH1 phenotype-specific requirements was identified.

PP1 No segregation data were identified to show co-segregation with disease across informative meioses.

PP3 Available computational evidence does not support applying PP3.

Benign

BA1 Population frequency does not reach the CDH1 BA1 threshold.

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.

BS3 No variant-specific functional RNA study demonstrating no impact on transcript composition was identified, so BS3 is not applied.

BS4 No family data showing lack of segregation with disease were identified.

BP4 Available computational evidence does not justify BP4 under the CDH1 rule.

BP5 No alternate pathogenic or likely pathogenic variant in another HDGC-associated gene was identified to explain the phenotype, so BP5 is not applied.

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.

N/A · 11 PS1 · PS4 · PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

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.

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.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0094% · 152 / 1,613,954
3 hom · FAF 0.14%

African/African American 122 / 75,034	0.16% 3 hom
Remaining individuals 15 / 62,506	0.024%
Admixed American 11 / 59,992	0.018%
European (non-Finnish) 4 / 1,179,876	0.00034%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.013% · 37 / 282,862
0 hom · FAF 0.082%

African/African American 28 / 24,972	0.11%
Admixed American 8 / 35,440	0.023%
Remaining individuals 1 / 7,224	0.014%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Triaged references · 9 PMIDs not cited in assessment

15322508 ↗ International variation. CLINVAR

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. CLINVAR

26123647 ↗ Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

27978560 ↗ Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. CLINVAR

28135145 ↗ Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. CLINVAR

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. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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