Variant classification summary

NM_004360.5:c.48+6_48+7delinsTT

CDH1 · NP_004351.1:p.? · NM_004360.5

GRCh37: chr16:68771372 CC>TT · GRCh38: chr16:68737469 CC>TT

Gene: CDH1 Transcript: NM_004360.5

Final call

VUS

PM2 supporting

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.?

gnomAD AF

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004360.5:c.48+6_48+7delinsTT is an intronic variant affecting positions +6 and +7 of CDH1 intron 1, outside the canonical splice consensus sequence.

2

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the CDH1 VCEP PM2_Supporting criterion (≤1 in 100,000 alleles).

3

SpliceAI predicts no significant splice impact (max delta score 0.06). However, only SpliceAI data is available among the seven splicing predictors specified by the CDH1 VCEP, which is insufficient to meet PP3 or BP4 thresholds requiring at least three concordant predictors.

4

No RNA functional studies, de novo occurrence data, case-control data, co-segregation data, or family studies meeting HDGC criteria were identified for this variant.

5

This variant has been reported in ClinVar as Likely benign (VariationID 136068) with a 1-star review status (criteria provided, single submitter). The ClinVar-associated publications are clinical practice guidelines and policy statements that do not provide variant-specific evidence.

6

With only PM2_Supporting met and no other pathogenic or benign criteria satisfied, this variant is classified as a Variant of Uncertain Significance under the CDH1 VCEP framework (v3.1). The ClinVar Likely benign classification has low evidentiary weight (1-star) and cannot independently drive a benign classification.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_004360.5:c.48+6_48+7delinsTT is an intronic variant at positions +6 and +7 of intron 1, outside the canonical splice consensus (±1, ±2). The CDH1 VCEP PVS1 decision tree applies PVS1_Strong to canonical splice site variants only; this variant does not disrupt the canonical splice donor or acceptor. SpliceAI predicts no significant splice impact (max delta score 0.06). No RNA studies are available to demonstrate an effect on transcript composition.	spliceai cspec pvs1_variant_assessment
PS1	N/A	PS1 is declared Not Applicable by the CDH1 VCEP (ClinGen CDH1 Expert Panel Specifications v3.1).	cspec
PS2	Not met	No de novo occurrence data identified for NM_004360.5:c.48+6_48+7delinsTT. The CDH1 VCEP requires patients meeting HDGC individual phenotype criteria with parental confirmation. No such reports were found in the literature or ClinVar submissions.	clinvar
PS3	Not met	The CDH1 VCEP PS3 criterion requires RNA assay data demonstrating abnormal transcripts (out-of-frame for strong, in-frame for moderate). No RNA functional studies were identified for NM_004360.5:c.48+6_48+7delinsTT. SpliceAI predicts no significant splice impact (max delta 0.06), and no experimental RNA data is available to evaluate transcript composition.	spliceai cspec
PS4	Not met	The CDH1 VCEP PS4 criterion requires families meeting HDGC criteria (1 family = supporting, 2-3 = moderate, 4-15 = strong, ≥16 = very strong). No case-level data identifying families with HDGC meeting the 2020 updated clinical practice guidelines (PMID: 32758476) were found for this variant. The ClinVar-associated publications are clinical practice guidelines and policy statements that do not report individual cases with this variant.	clinvar cspec
PS5	N/A	PS5 is not defined in the CDH1 VCEP criteria (v3.1) and no reputable source has recently reported this variant as pathogenic. ClinVar classification is Likely benign (1-star).	cspec clinvar
PM1	N/A	PM1 is declared Not Applicable by the CDH1 VCEP (ClinGen CDH1 Expert Panel Specifications v3.1).	cspec
PM2	Met	NM_004360.5:c.48+6_48+7delinsTT is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the CDH1 VCEP PM2_Supporting criterion (≤1 in 100,000 alleles). The VCEP specifies PM2 at supporting strength with the requirement that coverage of CDH1 in the population database be at least 30x.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM4	N/A	The CDH1 VCEP restricts PM4 to stop-loss variants only (example: c.2647T>C, p.Ter883Glnext*29). NM_004360.5:c.48+6_48+7delinsTT is an intronic indel, not a stop-loss variant.	cspec
PM5	N/A	The CDH1 VCEP repurposes PM5_Supporting 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), with site-specific recommendations for canonical splicing variants. NM_004360.5:c.48+6_48+7delinsTT is an intronic indel at positions +6/+7, which is neither a nonsense/frameshift variant nor a canonical splice site variant (±1, ±2). The VCEP PM5 rule does not apply.	cspec pm5_candidates
PM6	Not met	The CDH1 VCEP PM6 criterion requires patients meeting HDGC individual phenotype criteria without parental confirmation. No such de novo occurrence data was identified for NM_004360.5:c.48+6_48+7delinsTT.	clinvar
PP1	Not met	No co-segregation data is available for NM_004360.5:c.48+6_48+7delinsTT. The CDH1 VCEP requires 3-4 informative meioses for supporting, 5-6 for moderate, and ≥7 for strong PP1. No family studies with this variant were identified.	cspec
PP2	N/A	PP2 is declared Not Applicable by the CDH1 VCEP (ClinGen CDH1 Expert Panel Specifications v3.1).	cspec
PP3	Not met	The CDH1 VCEP PP3 criterion requires at least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK) for supporting strength, or a well-characterized variant at the same splice site with similar/worse predictions for moderate. Only SpliceAI data is available, which shows a max delta score of 0.06 (no significant splice impact). Insufficient predictor data to meet the VCEP threshold.	spliceai cspec
PP4	N/A	PP4 is declared Not Applicable by the CDH1 VCEP (ClinGen CDH1 Expert Panel Specifications v3.1).	cspec
PP5	N/A	PP5 is declared Not Applicable by the CDH1 VCEP per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. The ClinVar entry (VariationID 136068) is classified as Likely benign with a 1-star review status (criteria provided, single submitter), which does not meet the 3-star expert panel threshold for the global PP5 override.	cspec clinvar
BA1	Not met	The CDH1 VCEP BA1 criterion requires a MAF cutoff of 0.2%. NM_004360.5:c.48+6_48+7delinsTT is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, falling well below the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	The CDH1 VCEP BS1 criterion requires a MAF cutoff of 0.1%. NM_004360.5:c.48+6_48+7delinsTT is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, falling below the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	The CDH1 VCEP BS2 requires the variant to be seen in ≥10 individuals without GC, DGC, SRC tumors, or LBC with families not suggestive of HDGC (strong), or ≥3 individuals (supporting). No such clinical observation data is available for this variant.	cspec
BS3	Not met	The CDH1 VCEP BS3 criterion requires functional RNA studies demonstrating no impact on transcript composition and is restricted to synonymous, intronic, or non-coding variants. No RNA functional studies were identified for NM_004360.5:c.48+6_48+7delinsTT. SpliceAI prediction alone (max delta 0.06) does not constitute a functional study under the VCEP rule.	spliceai cspec
BS4	Not met	No segregation data is available for NM_004360.5:c.48+6_48+7delinsTT to evaluate lack of segregation among affected family members.	cspec
BP1	N/A	BP1 is declared Not Applicable by the CDH1 VCEP (ClinGen CDH1 Expert Panel Specifications v3.1).	cspec
BP2	Not met	The CDH1 VCEP BP2 requires observation of the variant in trans with a known pathogenic variant (strong) or in cis/unknown phase with a pathogenic variant, or in the homozygous state in gnomAD (supporting). No such evidence is available for this variant. The variant is absent from gnomAD and no phase data exists.	gnomad_v2 gnomad_v4 cspec
BP3	N/A	BP3 is declared Not Applicable by the CDH1 VCEP. This criterion applies to in-frame deletions/insertions in repetitive regions without known function, and the VCEP has determined it is not applicable for CDH1.	cspec
BP4	Not met	The CDH1 VCEP BP4 criterion requires at least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK) suggesting no impact. Only SpliceAI data is available (max delta 0.06, predicting no significant splice impact). A single predictor is insufficient to meet the VCEP threshold of three concordant predictors.	spliceai cspec
BP5	Not met	The CDH1 VCEP BP5 criterion 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 diagnosis was identified for the individual carrying this variant.	cspec
BP6	N/A	BP6 is declared Not Applicable by the CDH1 VCEP per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. The ClinVar entry (VariationID 136068) is classified as Likely benign with a 1-star review status (criteria provided, single submitter), which does not meet the 3-star expert panel threshold for the global BP6 override.	cspec clinvar
BP7	Not met	The CDH1 VCEP BP7 criterion applies to synonymous and intronic variants at or beyond +7 to -21 locations. NM_004360.5:c.48+6_48+7delinsTT affects intronic positions +6 and +7. Position +6 is not at or beyond the +7 threshold specified by the VCEP rule; therefore BP7 does not apply to this variant.	cspec
PM3	N/A	PM3 applies to recessive disorders. CDH1-associated hereditary diffuse gastric cancer is an autosomal dominant condition. PM3 is not applicable.

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