Variant classification summary

NM_004360.5:c.2053G>A

CDH1 · NP_004351.1:p.(Val685Met) · NM_004360.5

GRCh37: chr16:68857418 G>A · GRCh38: chr16:68823515 G>A

Gene: CDH1 Transcript: NM_004360.5

Final call

Likely Benign

BP2 supporting benign BP6 supporting benign

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.(Val685Met)

gnomAD AF

1.4872468581910121e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004360.5:c.2053G>A (p.Val685Met) is a missense variant in CDH1 exon 13. The ClinGen CDH1 Expert Panel has classified this variant as Likely benign (ClinVar Variation ID: 133847).

2

The variant is present in gnomAD population databases at low frequency: 4/251,468 alleles in v2.1 (AF 0.00159%) and 24/1,613,720 alleles in v4.1 (AF 0.00149%), with one homozygote reported in v4.1. These frequencies exceed the CDH1 VCEP PM2 threshold of ≤1/100,000 alleles, and the homozygote observation meets BP2_Supporting under the VCEP rules.

3

SpliceAI predicts no significant splicing impact (max delta score 0.11). In silico protein predictors show borderline scores (REVEL 0.47; BayesDel -0.1394), but per CDH1 VCEP, protein-based computational models are not used for PP3/BP4 assessment.

4

No variant-specific functional studies, segregation data, de novo reports, or case-control studies were identified in the reviewed literature. Six full-text papers and 10 additional abstracts were reviewed; none mention NM_004360.5:c.2053G>A or p.Val685Met.

5

One homozygote in gnomAD v4.1 meets CDH1 VCEP BP2_Supporting ('observed in the homozygous state in gnomAD'), providing a single line of benign evidence. No other ACMG criteria are met with the available evidence. Most criteria remain unassessed due to lack of variant-specific functional, segregation, or clinical phenotype data.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 applies to null variants (nonsense, frameshift, canonical splice sites). NM_004360.5:c.2053G>A is a missense variant (p.Val685Met) in exon 13 and does not fall into any PVS1 null-variant bucket. The CDH1 VCEP PVS1 decision tree is not applicable to missense substitutions.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 is marked Not Applicable for this VCEP per the ClinGen CDH1 Expert Panel Specifications v3.1.0.	cspec
PS2	Not assessed	No de novo occurrence data identified for this variant. PS2 requires confirmed de novo in a patient meeting HDGC individual phenotype criteria with parental confirmation. No such data found in ClinVar submissions, literature, or other sources.
PS3	Not assessed	Per CDH1 VCEP, PS3 requires RNA assay demonstrating abnormal transcripts. This is a missense variant with SpliceAI max delta score of 0.11 (no predicted splicing impact). No variant-specific functional RNA studies identified in the literature. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.	spliceai oncokb
PS4	Not met	PS4 requires families meeting HDGC criteria. The ClinGen CDH1 Expert Panel classified this variant as Likely benign, indicating no enrichment in affected individuals versus controls. No published case-control study demonstrates significant enrichment. Population data show the variant at low frequency in gnomAD, inconsistent with a highly penetrant pathogenic variant.	clinvar gnomad_v2 gnomad_v4
PS5	Not assessed	No alternative nucleotide change at c.2053 has been reported as pathogenic. No comparator data available to assess whether a different substitution at the same position is established as pathogenic.
PM1	N/A	PM1 is marked Not Applicable for this VCEP per the ClinGen CDH1 Expert Panel Specifications v3.1.0.	cspec
PM2	Not met	Per CDH1 VCEP, PM2_Supporting requires ≤1 out of 100,000 alleles in the gnomAD cohort. gnomAD v2.1: 4/251,468 alleles (1.59 per 100,000), exceeding the threshold. gnomAD v4.1: 24/1,613,720 alleles (1.49 per 100,000), also exceeding the threshold. Additionally, in gnomAD v4.1 Admixed American subpopulation: 8/60,000 alleles (13.3 per 100,000), exceeding the subpopulation rule of ≤1 per 50,000 when ≥2 individuals are present.	gnomad_v2 gnomad_v4
PM5	N/A	Per CDH1 VCEP v3.1.0, PM5 is repurposed for nonsense and frameshift variants predicted/proven to undergo NMD or located upstream of the last known pathogenic truncating variant (c.2506G>T, p.Glu836Ter). This is a missense variant and does not qualify for VCEP-specified PM5_Supporting. Classic same-residue missense PM5 is not applied under this VCEP.	cspec pm5_candidates
PM6	Not assessed	No assumed de novo occurrences identified. PM6 requires patients meeting HDGC individual phenotype criteria without parental confirmation. No such reports found in ClinVar submissions or literature.
PP1	Not assessed	No cosegregation data identified for this variant. PP1 requires informative meioses across families. No published segregation studies found in the literature or ClinVar submissions.
PP2	N/A	PP2 is marked Not Applicable for this VCEP per the ClinGen CDH1 Expert Panel Specifications v3.1.0.	cspec
PP3	Not met	Per CDH1 VCEP, PP3 is limited to splicing predictions only (do not use protein-based computational models). SpliceAI max delta score is 0.11, which is below the threshold for predicted splicing impact. No additional in silico splicing predictors (MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK) are available in the evidence record. At least three predictors in agreement are required for PP3_Supporting. Criterion not met.	spliceai
PP4	N/A	PP4 is marked Not Applicable for this VCEP per the ClinGen CDH1 Expert Panel Specifications v3.1.0.	cspec
PP5	N/A	PP5 is marked Not Applicable for this VCEP per the ClinGen CDH1 Expert Panel Specifications v3.1.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	Per CDH1 VCEP, BA1 requires MAF ≥0.2%. gnomAD v2.1 AF: 0.00159% (4/251,468). gnomAD v4.1 AF: 0.00149% (24/1,613,720). Highest subpopulation AF: 0.0133% (Admixed American, gnomAD v4.1). All frequencies are well below the 0.2% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Per CDH1 VCEP, BS1 requires MAF ≥0.1%. gnomAD v2.1 AF: 0.00159%. gnomAD v4.1 AF: 0.00149%. Highest subpopulation AF: 0.0133% (Admixed American, v4.1). All frequencies are below the 0.1% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	BS2 requires phenotype data on individuals carrying the variant — specifically, individuals without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer, and whose families do not suggest HDGC. gnomAD population data lack individual-level phenotype information. gnomAD v4.1 contains 24 heterozygous individuals and 1 homozygote, but the clinical status of these individuals is unknown. Cannot apply BS2 without phenotype data.	gnomad_v4
BS3	Not assessed	Per CDH1 VCEP, BS3 requires functional RNA studies demonstrating no impact on transcript composition and is limited to synonymous, intronic, or non-coding variants. This is a missense variant. No variant-specific functional benign studies identified in the literature.
BS4	Not assessed	No segregation data available for this variant. BS4 requires lack of segregation in affected family members. No published family studies identified in the literature or ClinVar submissions.
BP1	N/A	BP1 is marked Not Applicable for this VCEP per the ClinGen CDH1 Expert Panel Specifications v3.1.0.	cspec
BP2	Met	Per CDH1 VCEP BP2_Supporting rule: 'observed in the homozygous state in gnomAD.' gnomAD v4.1 reports 1 homozygote for this variant (total_hom = 1). This meets the VCEP-specified threshold for BP2 at the Supporting benign level. The single homozygote observation in a large population database (1,613,720 alleles) is consistent with a variant unlikely to cause a highly penetrant dominant disorder like HDGC. Note: a single homozygote in gnomAD may represent a technical artifact; the expert panel's Likely benign classification provides orthogonal support.	gnomad_v4 clinvar
BP4	Not met	Per CDH1 VCEP, BP4 is limited to splicing predictions only and requires at least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK). Only SpliceAI data is available (max delta 0.11, no splicing impact). A single predictor is insufficient to meet the VCEP requirement of three concordant predictors.	spliceai
BP5	Not assessed	BP5 requires identification of a pathogenic/likely pathogenic variant in an alternate gene known to cause HDGC (per VCEP: currently only CTNNA1). No data on alternate molecular diagnoses available for individuals carrying this variant.
BP6	Met	Expert panel Clingen Gastric Cancer Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	N/A	Per CDH1 VCEP, BP7 applies to synonymous and intronic variants at or beyond +7 to -21 positions. NM_004360.5:c.2053G>A is a missense variant (p.Val685Met) in exon 13. BP7 is not applicable to missense substitutions.	cspec

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