NM_004360.5:c.1138-3C>T

CDH1 · NP_004351.1:p.? · NM_004360.5

GRCh37: chr16:68847213 C>T · GRCh38: chr16:68813310 C>T

Gene: CDH1 Transcript: NM_004360.5

Final call

Likely Benign

BS1 strong BP2 supporting BP6 supporting benign

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.?

gnomAD AF

9.41786444966833e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.

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	Not met	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. Available computational evidence also does not suggest a major splice disruption, so PVS1 is not applied.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	PS1 is not applicable for CDH1 under this specification.	cspec
PS2	Not assessed	No confirmed de novo observation meeting the CDH1 phenotype-specific requirements was identified.	cspec
PS3	Not assessed	No variant-specific RNA study demonstrating an abnormal out-of-frame or in-frame transcript was identified, so PS3 is not applied.	cspec
PS4	N/A	PS4 is not applied because this variant meets BS1, and the CDH1 specification states that PS4 cannot be applied to variants that meet BS1 or BA1.	cspec gnomad_v2 gnomad_v4
PM1	N/A	PM1 is not applicable for CDH1 under this specification.	cspec
PM2	Not met	Population frequency is above the CDH1 PM2 threshold. In gnomAD v4.1, the total allele frequency is 0.0000942 (152/1613954), above the required threshold of ≤0.00001, and the African/African American subpopulation frequency is 0.0016259 (122/75034), far above the ≤0.00002 subpopulation threshold when multiple alleles are present.	cspec gnomad_v4 gnomad_v2
PM3	N/A	PM3 is not applicable for CDH1 under this specification.	cspec
PM4	N/A	PM4 is limited to stop-loss variants in CDH1, and this intronic variant is not a stop-loss variant.	cspec
PM5	N/A	PM5 is not applied. In CDH1, PM5 is repurposed away from classic same-residue missense logic, and this intronic variant is not eligible for the truncating or canonical-splicing PM5 framework described for CDH1.	cspec pm5_candidates
PM6	Not assessed	No assumed de novo observation meeting the CDH1 phenotype-specific requirements was identified.	cspec
PP1	Not assessed	No segregation data were identified to show co-segregation with disease across informative meioses.	cspec
PP2	N/A	PP2 is not applicable for CDH1 under this specification.	cspec
PP3	Not assessed	Available computational evidence does not support applying PP3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the retrieved evidence does not provide the three concordant splicing predictors required by the CDH1 specification for PP3.	cspec spliceai
PP4	N/A	PP4 is not applicable for CDH1 under this specification.	cspec
PP5	N/A	PP5 is not used under this specification.	cspec
BA1	Not met	Population frequency does not reach the CDH1 BA1 threshold. The highest observed gnomAD v4.1 population frequency is 0.0016259 (0.16259%) in African/African American individuals, which is below the BA1 cutoff of 0.2%.	cspec gnomad_v4 gnomad_v2
BS1	Met	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).	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	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.	cspec
BS3	Not assessed	No variant-specific functional RNA study demonstrating no impact on transcript composition was identified, so BS3 is not applied.	cspec
BS4	Not assessed	No family data showing lack of segregation with disease were identified.	cspec
BP1	N/A	BP1 is not applicable for CDH1 under this specification.	cspec
BP2	Met	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.	cspec gnomad_v4
BP3	N/A	BP3 is not applicable for CDH1 under this specification.	cspec
BP4	Not assessed	Available computational evidence does not justify BP4 under the CDH1 rule. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the retrieved evidence does not include the three concordant accepted splicing predictors required by the CDH1 specification.	cspec spliceai
BP5	Not assessed	No alternate pathogenic or likely pathogenic variant in another HDGC-associated gene was identified to explain the phenotype, so BP5 is not applied.	cspec
BP6	Met	Expert panel Clingen Gastric Cancer Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Not met	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.	cspec

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