Classification rationale

BA1BP6 Benign

CDH1 c.1888C>G

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.¹ 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 v4.1.² 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 BP4.³

BA1 + BP6 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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

CDH1 NM_004360.5

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

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.

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.

🇨🇦 CA

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).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.017% · 267 / 1,614,146
0 hom · FAF 0.5%

East Asian 252 / 44,882	0.56%
Remaining individuals 7 / 62,510	0.011%
South Asian 8 / 91,080	0.0088%

+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.036% · 101 / 282,868
0 hom · FAF 0.41%

East Asian 97 / 19,950	0.49%
Remaining individuals 3 / 7,226	0.042%
South Asian 1 / 30,616	0.0033%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish))

gnomAD Canada 🇨🇦

0.033% · 6 / 18,418
0 hom · FAF 0.061%

East Asian 3 / 1,338	0.22%
South Asian 2 / 1,362	0.15%
Remaining individuals 1 / 1,138	0.088%

+ 6 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.345. BayesDel score = -0.164621.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55733235, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

23431106 ↗ Novel CDH1 germline mutations identified in Chinese gastric cancer patients. CLINVAR

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. 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

26086041 ↗ Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry. CLINVAR

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

26757417 ↗ Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing. CLINVAR

32566746 ↗ Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

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