Variant classification summary

NM_004360.5:c.48+7C>T

CDH1 · NP_004351.1:p.? · NM_004360.5

GRCh37: chr16:68771373 C>T · GRCh38: chr16:68737470 C>T

Gene: CDH1 Transcript: NM_004360.5

Final call

Likely Benign

BS3 strong benign BP7 supporting benign

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.?

gnomAD AF

7.157562680728458e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004360.5:c.48+7C>T is an intronic variant at position +7 of intron 1 in CDH1. It has been reported in ClinVar as Likely benign by four clinical laboratories (ClinVar ID 142318, 1-star review status).

2

This variant is present at very low frequency in gnomAD population databases: 2 of 130,982 alleles in v2.1 (0.00153%) and 11 of 1,536,836 alleles in v4.1 (0.00072%), with no homozygotes observed.

3

Functional RNA studies by Garziera et al. (2013, PMID 24204729) evaluated the splicing impact of c.48+7C>T using RT-PCR on peripheral blood mononuclear cells from a heterozygous carrier. The transcript was normal in size and sequence compared to wild-type controls, with no aberrant splicing products, protein truncations, or frameshifts detected. These findings satisfy BS3 at strong strength per CDH1 VCEP specifications.

4

The variant's intronic position at +7 meets the CDH1 VCEP BP7 rule for intronic variants at or beyond the +7 position, providing supporting evidence for a benign interpretation.

5

SpliceAI predicts no significant splice impact (max delta score = 0.02), consistent with the normal transcript observed in functional RNA studies.

6

PS3 is not met because the functional data demonstrated no abnormal transcripts; the evidence direction is benign rather than pathogenic.

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	NM_004360.5:c.48+7C>T is an intronic variant at the +7 position of intron 1. This is not a canonical ±1,2 splice site variant and does not fall into the CDH1 VCEP PVS1 decision tree for null variants. Per PVS1 variant assessment, this variant is classified in the 'other' bucket with no canonical splice consensus disruption.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 is designated as Not Applicable by the ClinGen CDH1 Expert Panel Specification Version 3.1.	cspec
PS2	Not assessed	No de novo data (with confirmed maternity and paternity) available for NM_004360.5:c.48+7C>T. None of the reviewed publications report de novo occurrence of this variant in a patient meeting HDGC phenotype criteria.
PS3	Not met	The only available functional data for this variant (Garziera et al. 2013, PMID 24204729) demonstrated normal CDH1 transcript composition by RT-PCR with no aberrant splicing or protein truncations. Per CDH1 VCEP, PS3 requires RNA assay demonstrating abnormal out-of-frame or in-frame transcripts. The experimental evidence showed no splicing defect, which is contrary to what PS3 requires.	PMID:24204729
PS4	Not assessed	No case-family data available indicating that individuals or families harboring NM_004360.5:c.48+7C>T meet HDGC criteria. The variant was identified in a single AMAG patient without gastric cancer (PMID 24204729), not in HDGC families.	PMID:24204729
PS5	Not assessed	PS5 is not a recognized ACMG/AMP 2015 criterion. It does not appear in standard ACMG/AMP guidelines nor in the ClinGen CDH1 VCEP specification. No assessment performed.
PM1	N/A	PM1 is designated as Not Applicable by the ClinGen CDH1 Expert Panel Specification Version 3.1.	cspec
PM2	Not met	Per CDH1 VCEP PM2 rule: variant must be present at ≤1 per 100,000 alleles in gnomAD. In gnomAD v4.1, the variant is present at 7.16e-06 (11/1,536,836), meeting the total cohort threshold. However, the variant is present in ≥2 individuals within the Remaining subpopulation (2/59,902 = 3.34e-05), which exceeds the required ≤1 per 50,000 (2e-05) subpopulation threshold. In gnomAD v2.1, the variant is present at 1.53e-05 (2/130,982), exceeding the ≤1 per 100,000 total threshold. PM2 is not met in either gnomAD version.	gnomad_v2 gnomad_v4
PM5	N/A	The CDH1 VCEP repurposes PM5 for nonsense and frameshift variants predicted/proven to undergo NMD or located upstream of the last known pathogenic truncating variant. NM_004360.5:c.48+7C>T is an intronic substitution, not a nonsense or frameshift variant. PM5 candidate search confirmed not applicable.	pm5_candidates cspec
PM6	Not assessed	No assumed de novo (without parental confirmation) data available for NM_004360.5:c.48+7C>T. None of the reviewed publications report de novo occurrence of this variant in a patient meeting HDGC phenotype criteria.
PP1	Not assessed	No co-segregation data available for NM_004360.5:c.48+7C>T. No family studies with informative meioses were identified in the literature.
PP2	N/A	PP2 is designated as Not Applicable by the ClinGen CDH1 Expert Panel Specification Version 3.1.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact (max delta = 0.02). The only available functional RNA data (PMID 24204729) confirmed no aberrant splicing. Only one in silico splicing predictor (SpliceAI) is available in the evidence packet; the CDH1 VCEP requires at least three in silico splicing predictors in agreement for supporting strength. No well-characterized pathogenic variant at the same splice site exists to support moderate strength. PP3 is not met.	spliceai PMID:24204729
PP4	N/A	PP4 is designated as Not Applicable by the ClinGen CDH1 Expert Panel Specification Version 3.1.	cspec
PP5	N/A	PP5 is designated as Not Applicable by the ClinGen CDH1 Expert Panel Specification Version 3.1. The ClinVar entry for this variant (VCV000142318) has a 1-star review status (criteria provided, single submitter), which does not meet the 3-star expert panel threshold for the global PP5/BP6 override rule.	cspec clinvar
BA1	Not met	The CDH1 VCEP BA1 threshold is an allele frequency greater than 0.2% (MAF > 0.002). In gnomAD v4.1, the global allele frequency is 7.16e-06 (0.00072%), well below 0.2%. In gnomAD v2.1, the global AF is 1.53e-05 (0.00153%), also well below 0.2%. The variant is too rare to meet BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The CDH1 VCEP BS1 threshold is an allele frequency greater than 0.1% (MAF > 0.001). In gnomAD v4.1, the global allele frequency is 7.16e-06 (0.00072%), well below 0.1%. In gnomAD v2.1, the global AF is 1.53e-05 (0.00153%), also well below 0.1%. The variant is too rare to meet BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	Insufficient clinical phenotype data to determine whether the 11 individuals in gnomAD v4 (or 2 in gnomAD v2) are free of gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer, and whether their families lack features suggestive of HDGC. The one individual carrying this variant described in PMID 24204729 was an autoimmune metaplastic atrophic gastritis patient without gastric cancer, but a single observation is insufficient to meet the ≥3 (supporting) or ≥10 (strong) threshold.	gnomad_v2 gnomad_v4 PMID:24204729
BS3	Met	Functional RNA studies (Garziera et al. 2013, PMID 24204729) demonstrated no impact on CDH1 transcript composition for NM_004360.5:c.48+7C>T. RT-PCR of exons 1-5 from peripheral blood mononuclear cells of the variant carrier produced a normal-sized 768 bp fragment identical to wild-type controls. Bidirectional sequencing confirmed the absence of aberrant transcripts. No protein truncations or frameshifts were detected. Per CDH1 VCEP BS3 rule: 'Functional RNA studies demonstrating no impact on transcript composition' applies at Strong strength.	PMID:24204729
BS4	Not assessed	No segregation data available for NM_004360.5:c.48+7C>T. Lack of segregation in affected family members cannot be evaluated without family studies.
BP1	N/A	BP1 is designated as Not Applicable by the ClinGen CDH1 Expert Panel Specification Version 3.1. Additionally, this is an intronic variant, not a missense variant.	cspec
BP2	Not assessed	No evidence of NM_004360.5:c.48+7C>T observed in trans with a known pathogenic CDH1 variant (phase confirmed), nor observed in the homozygous state in an individual without personal/family history of DGC, LBC, or SRC tumors. Not observed in the homozygous state in gnomAD. Insufficient data to assess BP2.	gnomad_v2 gnomad_v4
BP4	Not met	The CDH1 VCEP BP4 rule requires at least three in silico splicing predictors in agreement showing no impact. Only SpliceAI is available in the evidence packet (max delta = 0.02, no predicted splice impact). Although the available predictor supports no splicing effect and the functional RNA data (PMID 24204729) confirms this, the VCEP rule strictly requires ≥3 predictors. Without additional predictors (MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK), BP4 cannot be applied.	spliceai PMID:24204729
BP5	Not met	Per CDH1 VCEP, BP5 applies when a pathogenic/likely pathogenic variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1). No evidence of an alternate molecular basis for disease was identified in the case materials. BP5 is not met.
BP6	N/A	BP6 is designated as Not Applicable by the ClinGen CDH1 Expert Panel Specification Version 3.1. The ClinVar entry for this variant (VCV000142318) has a 1-star review status (criteria provided, single submitter), which does not meet the 3-star expert panel threshold for the global PP5/BP6 override rule.	cspec clinvar
BP7	Met	NM_004360.5:c.48+7C>T is an intronic variant located at the +7 position of intron 1. Per CDH1 VCEP BP7 rule: 'Synonymous and intronic variants at or beyond +7 to -21 locations.' The variant at +7 falls exactly at the boundary of this rule. The CSPEC instructions note that the CDH1 rule specification does not require a conservation prediction and that BP7 may be used with BP4 to classify variants meeting both criteria as likely benign. Here BP7 is applied independently based on the positional rule.	cspec

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