Variant classification summary

NM_004360.5:c.1888C>G

CDH1 · NP_004351.1:p.(Leu630Val) · NM_004360.5

GRCh37: chr16:68856080 C>G · GRCh38: chr16:68822177 C>G

Gene: CDH1 Transcript: NM_004360.5

Final call

Benign

BA1 stand-alone benign BP6 supporting benign

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.(Leu630Val)

gnomAD AF

0.00016541254632480582 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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	This is a missense variant, not a nonsense, frameshift, canonical splice-site, initiation-codon, or deletion variant. Available CDH1 PVS1 guidance and the variant-level PVS1 assessment therefore do not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 is not used in the CDH1 specification.	cspec
PS2	Not assessed	No confirmed de novo occurrence in an individual meeting HDGC phenotype criteria was identified.	cspec clinvar
PS3	Not assessed	No RNA study showing an abnormal out-of-frame or in-frame transcript for this variant was identified. Available evidence does not support applying PS3.	cspec spliceai oncokb
PS4	Not met	This variant is too common in population databases for PS4 under the CDH1 specification, and no qualifying HDGC-family count was identified. The highest observed East Asian frequency is 0.48622% in gnomAD v2.1 and 0.56147% in gnomAD v4.1, which is above the CDH1 BS1 and BA1 thresholds and argues against enrichment in affected individuals.	cspec gnomad_v2 gnomad_v4 clinvar
PM1	N/A	PM1 is not used in the CDH1 specification.	cspec hotspots
PM2	Not met	Population frequency is well above the CDH1 PM2_Supporting threshold of no more than 1 in 100,000 alleles overall and no more than 1 in 50,000 alleles in a subpopulation with at least 2 observations. This variant is present at 101/282868 alleles in gnomAD v2.1, 267/1614146 alleles in gnomAD v4.1, and 97/19950 East Asian alleles in gnomAD v2.1.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not used in the CDH1 specification.	cspec
PM4	N/A	In CDH1, PM4 is reserved for stop-loss variants. This variant is a missense change and does not meet that rule.	cspec
PM5	N/A	In the CDH1 specification, PM5 is repurposed for truncating or specific splice-related logic rather than classic same-residue missense comparison. The PM5 review artifact found that classic same-residue PM5 searching is not eligible for this missense variant.	cspec pm5_candidates
PM6	Not assessed	No assumed de novo occurrence in an individual meeting HDGC phenotype criteria was identified.	cspec clinvar
PP1	Not assessed	No segregation data were identified to show co-segregation with HDGC-related disease.	cspec clinvar
PP2	N/A	PP2 is not used in the CDH1 specification.	cspec
PP3	Not met	Available computational evidence does not support a splice-disrupting effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, and CDH1 PP3 is based on splicing evidence rather than protein-based missense prediction. REVEL 0.345 and BayesDel -0.164621 were available but are not used to apply CDH1 PP3 for missense variants.	cspec spliceai revel bayesdel
PP4	N/A	PP4 is not used in the CDH1 specification.	cspec
PP5	N/A	PP5 is not used in the CDH1 specification.	cspec clinvar
BA1	Met	Population frequency exceeds the CDH1 BA1 threshold of 0.2%. The highest observed East Asian frequency is 0.48622% in gnomAD v2.1 (97/19950 alleles) and 0.56147% in gnomAD v4.1 (252/44882 alleles), both in subpopulations with more than 2000 alleles and more than 5 observed variant alleles.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not assessed	Population frequency also exceeds the CDH1 BS1 threshold of 0.1%, but BA1 is already met at the higher benign population strength and is the population criterion applied here.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No phenotyped series of at least 3 or 10 unaffected carriers without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer was identified, so BS2 cannot be assessed from the available evidence.	cspec clinvar
BS3	N/A	In the CDH1 specification, BS3 is limited to synonymous, intronic, or non-coding variants with RNA evidence showing no impact on transcript composition. This variant is missense, so BS3 is not applicable.	cspec spliceai
BS4	Not assessed	No family data showing lack of segregation with disease were identified.	cspec clinvar
BP1	N/A	BP1 is not used in the CDH1 specification.	cspec
BP2	Not assessed	No phase information showing this variant in cis or trans with a pathogenic variant, and no homozygous observation in gnomAD, were identified.	cspec gnomad_v2 gnomad_v4
BP3	N/A	BP3 is not used in the CDH1 specification.	cspec
BP4	N/A	BP4 is not applied to missense variants in the CDH1 specification. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, and protein-based missense predictors such as REVEL 0.345 and BayesDel -0.164621 are not used to apply CDH1 BP4.	cspec spliceai revel bayesdel
BP5	Not assessed	No alternate pathogenic or likely pathogenic variant in another HDGC gene was identified to explain the phenotype instead of CDH1.	cspec clinvar
BP6	Met	Expert panel Clingen Gastric Cancer Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	N/A	BP7 is restricted to synonymous and qualifying intronic variants. This variant is a missense change and does not meet BP7.	cspec spliceai

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