Variant classification summary

NM_004360.5:c.1266A>G

CDH1 · NP_004351.1:p.(Gln422=) · NM_004360.5

GRCh37: chr16:68847344 A>G · GRCh38: chr16:68813441 A>G

Gene: CDH1 Transcript: NM_004360.5

Final call

VUS

BP7 supporting

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.(Gln422=)

gnomAD AF

9.29248275315201e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004360.5:c.1266A>G (p.Gln422=) is a synonymous variant in CDH1 exon 9.

2

SpliceAI predicts no impact on splicing (max delta score = 0.00).

3

BP7 (supporting) is applied per CDH1 CSPEC v3.1: synonymous variant without requirement for conservation prediction.

4

The variant is present in gnomAD at very low frequency: 3/251,488 alleles in v2.1 (0.00119%) and 15/1,614,208 alleles in v4.1 (0.00093%), with no homozygotes.

5

In ClinVar, this variant is classified as Likely benign by 7 clinical laboratories and as Benign by 1 clinical laboratory (ClinVar Variation ID: 185874, 1-star review status).

6

No pathogenic criteria are met. Only BP7 (supporting benign) is applicable. With a single supporting benign criterion, the formal ACMG/AMP classification is Variant of Uncertain Significance; however, the clinical consensus from 8 diagnostic laboratories supports a Likely benign interpretation for this synonymous variant with no predicted splice impact.

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.1266A>G is a synonymous variant (p.Gln422=) and does not meet the PVS1 null-variant criteria under the CDH1 CSPEC v3.1 decision tree, which covers nonsense, frameshift, canonical ±1,2 splice site, initiation codon, and exon deletion variants.	cspec pvs1_variant_assessment
PS1	N/A	PS1 is not applicable under the CDH1 CSPEC v3.1.	cspec
PS2	Not met	No de novo observations with confirmed maternity and paternity meeting HDGC individual phenotype criteria are available for this variant.
PS3	Not met	Under CDH1 CSPEC v3.1, PS3 is restricted to RNA assays demonstrating abnormal transcripts. No RNA studies have been performed for this variant. SpliceAI predicts no splice impact (max delta = 0.00).	spliceai
PS4	Not met	No families meeting HDGC criteria have been reported for this variant. The variant is a synonymous change classified as likely benign/benign in ClinVar by 8 clinical laboratories, inconsistent with a pathogenic enrichment in affected individuals.	clinvar
PS5	N/A	PS5 is not defined in the CDH1 CSPEC v3.1 criteria set.	cspec
PM1	N/A	PM1 is not applicable under the CDH1 CSPEC v3.1.	cspec
PM2	Not met	The variant is present in gnomAD at low frequency. In v2.1, it is observed in 3/251,488 alleles (0.00119%, ~1.19/100,000), which slightly exceeds the CDH1 CSPEC PM2_Supporting threshold of ≤1/100,000 alleles. In v4.1, it is observed in 15/1,614,208 alleles (0.00093%), but is present in 2/6,062 Middle Eastern alleles (0.033%), exceeding the subpopulation threshold of ≤1/50,000 when present in ≥2 individuals.	gnomad_v2 gnomad_v4
PM5	N/A	Under CDH1 CSPEC v3.1, PM5_Supporting is applicable only to nonsense and frameshift variants predicted to undergo NMD or located upstream of the last known pathogenic truncating variant. This is a synonymous variant.	cspec pm5_candidates
PM6	Not met	No assumed de novo observations (without parental confirmation) meeting HDGC individual phenotype criteria are available for this variant.
PP1	Not met	No cosegregation data with informative meioses are available for this variant.
PP2	N/A	PP2 is not applicable under the CDH1 CSPEC v3.1.	cspec
PP3	Not met	Under CDH1 CSPEC v3.1, PP3 requires at least three in silico splicing predictors in agreement. Only SpliceAI data is available (delta = 0.00, no splice impact). Without ≥3 independent splicing predictors, PP3 cannot be applied. Additionally, the CSPEC instructs not to use protein-based computational prediction models for missense variants, and this synonymous variant has no predicted splice impact.	spliceai
PP4	N/A	PP4 is not applicable under the CDH1 CSPEC v3.1.	cspec
PP5	N/A	PP5 is not for use under the CDH1 CSPEC v3.1 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No ClinVar 3-star expert panel submission exists to trigger the global PP5 override.	cspec clinvar
BA1	Not met	The CDH1 CSPEC BA1 threshold is MAF >0.2%. The highest observed frequency in gnomAD is 0.033% (Middle Eastern, gnomAD v4.1), well below the 0.2% cutoff. Additionally, the CSPEC requires ≥2,000 alleles and ≥5 variant alleles in the subpopulation; no subpopulation meets both criteria.	gnomad_v2 gnomad_v4
BS1	Not met	The CDH1 CSPEC BS1 threshold is MAF >0.1%. The highest observed frequency in gnomAD is 0.033% (Middle Eastern, v4.1), below the cutoff. Additionally, the CSPEC requires ≥2,000 alleles and ≥5 variant alleles in the subpopulation; no subpopulation meets both criteria.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires ≥10 individuals without gastric cancer, DGC, SRC tumors, or LBC and whose families do not suggest HDGC. While the variant is observed in 18 individuals across gnomAD (3 in v2.1, 15 in v4.1), phenotype data confirming absence of HDGC-related cancers are not available for these population cohorts.	gnomad_v2 gnomad_v4
BS3	Not met	Under CDH1 CSPEC v3.1, BS3 requires functional RNA studies demonstrating no impact on transcript composition. This synonymous variant has SpliceAI delta = 0.00 (predicting no splice impact), but no experimental RNA studies have been performed. In silico prediction alone does not satisfy the functional data requirement.	spliceai
BS4	Not met	No segregation data are available to assess lack of segregation in affected family members.
BP1	N/A	BP1 is not applicable under the CDH1 CSPEC v3.1.	cspec
BP2	Not met	No evidence of the variant in trans with a known pathogenic variant or in a homozygous state in an individual without HDGC-related cancer history. The variant has 0 homozygotes in gnomAD.	gnomad_v2 gnomad_v4
BP4	Not met	Under CDH1 CSPEC v3.1, BP4 requires at least three in silico splicing predictors in agreement. Only SpliceAI data is available (delta = 0.00, predicting no splice impact). Without ≥3 independent predictors, BP4 cannot be applied.	spliceai
BP5	Not met	BP5 applies when a pathogenic/likely pathogenic variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1). No such finding has been reported for individuals carrying this variant.
BP6	N/A	BP6 is not for use under the CDH1 CSPEC v3.1 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No ClinVar 3-star expert panel benign submission exists to trigger the global BP6 override.	cspec clinvar
BP7	Met	NM_004360.5:c.1266A>G is a synonymous variant (p.Gln422=) in exon 9. Under CDH1 CSPEC v3.1, BP7 applies to synonymous variants without requiring a conservation prediction. SpliceAI predicts no splice impact (max delta = 0.00), and the variant is located 54 nucleotides upstream of the exon 9 donor splice site, well outside the splice consensus region.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.