Variant classification summary

NM_004360.5:c.2077G>A

CDH1 · NP_004351.1:p.(Gly693Ser) · NM_004360.5

GRCh37: chr16:68857442 G>A · GRCh38: chr16:68823539 G>A

Gene: CDH1 Transcript: NM_004360.5

Final call

VUS

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.(Gly693Ser)

gnomAD AF

2.4784836636945516e-05 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004360.5:c.2077G>A (p.Gly693Ser) is a missense variant in CDH1 exon 13. Under the ClinGen CDH1 Expert Panel Specifications Version 3.1, no pathogenic or benign criteria are met. PVS1 is not applicable to missense variants. PM2 is not met because the variant exceeds the VCEP threshold of ≤1 per 100,000 alleles (gnomAD v2.1: ~4.2/100,000; v4.1: ~2.5/100,000). Population frequency is insufficient for BA1 (cutoff 0.2%) or BS1 (cutoff 0.1%). SpliceAI predicts no significant splicing impact (max delta 0.12), and PP3/BP4 are restricted to splicing predictors under the VCEP. No de novo, segregation, case-control, or functional data for this variant were identified among the four reviewed publications or ClinVar submissions. Multiple criteria are designated as Not Applicable by the CDH1 VCEP (PS1, PM1, PP2, PP4, BP1, PP5, BP6). The variant is classified as a Variant of Uncertain Significance.

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	PVS1 is not applicable to missense variants. NM_004360.5:c.2077G>A is a missense substitution (p.Gly693Ser) in exon 13 and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 application under the CDH1 VCEP modified decision tree.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1).	cspec
PS2	Not met	No de novo observation of NM_004360.5:c.2077G>A with parental confirmation meeting HDGC individual phenotype criteria has been identified in the reviewed literature or ClinVar submissions.
PS3	Not met	Under the CDH1 VCEP, PS3 can only be applied to demonstrate splicing defects via RNA assays. NM_004360.5:c.2077G>A is a missense variant with no evidence of splicing impact (SpliceAI max delta score 0.12). No RNA assay or functional data demonstrating abnormal transcripts have been reported for this variant.	spliceai
PS4	Not met	No families meeting HDGC criteria and harboring NM_004360.5:c.2077G>A have been identified in the reviewed literature. The variant is present in gnomAD at low frequency but no case-control or family-based association data exist.	gnomad_v2 gnomad_v4
PS5	Not met	ClinVar reports this variant as Benign (1 clinical laboratory), Likely benign (1 clinical laboratory), and Uncertain significance (1 clinical laboratory). No reputable source has reported this variant as pathogenic; the ClinVar consensus does not support PS5 application.	clinvar
PM1	N/A	PM1 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1.	cspec
PM2	Not met	Under the CDH1 VCEP, PM2_Supporting requires ≤1 allele per 100,000 in gnomAD. This variant is observed at 12/282,770 alleles (AF=0.0042%, ~4.2 per 100,000) in gnomAD v2.1 and 40/1,613,890 alleles (AF=0.0025%, ~2.5 per 100,000) in gnomAD v4.1, both exceeding the VCEP PM2_Supporting threshold.	gnomad_v2 gnomad_v4
PM5	N/A	Under the CDH1 VCEP, PM5 is repurposed to apply only to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant (c.2506G>T). NM_004360.5:c.2077G>A is a missense variant and does not meet these criteria.	cspec pm5_candidates
PM6	Not met	No patients with NM_004360.5:c.2077G>A meeting HDGC individual phenotype criteria (without parental confirmation) have been identified in the reviewed literature.
PP1	Not met	No co-segregation data across informative meioses in families harboring NM_004360.5:c.2077G>A have been identified in the reviewed literature.
PP2	N/A	PP2 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1.	cspec
PP3	Not met	Under the CDH1 VCEP, PP3 is restricted to splicing predictions only (at least three in silico splicing predictors in agreement) and protein-based models are not to be used for missense variants. SpliceAI shows no significant splice impact (max delta 0.12). No additional splicing predictors are available to demonstrate a deleterious splicing effect.	spliceai revel bayesdel
PP4	N/A	PP4 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1.	cspec
PP5	N/A	PP5 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The CDH1 VCEP BA1 allele frequency threshold is 0.2%. This variant has a global MAF of 0.0042% in gnomAD v2.1 and 0.0025% in gnomAD v4.1, both well below the BA1 cutoff.	gnomad_v2 gnomad_v4
BS1	Not met	The CDH1 VCEP BS1 allele frequency threshold is 0.1%. This variant has a global MAF of 0.0042% in gnomAD v2.1 and 0.0025% in gnomAD v4.1, both well below the BS1 cutoff.	gnomad_v2 gnomad_v4
BS2	Not met	The CDH1 VCEP requires observation in ≥3 individuals without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer whose families do not suggest HDGC. While this variant is present in gnomAD (12 heterozygotes in v2.1, 40 in v4.1), the phenotype of these carriers is unknown, precluding BS2 application.	gnomad_v2 gnomad_v4
BS3	N/A	Under the CDH1 VCEP, BS3 can only be used to demonstrate lack of splicing and can only be applied to synonymous, intronic, or non-coding variants. NM_004360.5:c.2077G>A is a missense variant, which is excluded from BS3 application.	cspec
BS4	Not met	No segregation data are available for NM_004360.5:c.2077G>A to evaluate lack of segregation in affected family members.
BP1	N/A	BP1 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not applicable for CDH1.	cspec
BP2	Not met	No homozygotes for NM_004360.5:c.2077G>A are observed in gnomAD (0 homozygotes in both v2.1 and v4.1), and no data on observation in trans with a known pathogenic variant are available.	gnomad_v2 gnomad_v4
BP4	N/A	Under the CDH1 VCEP, BP4 is restricted to splicing predictions only (at least three in silico splicing predictors in agreement) and is not applicable for missense variants.	cspec
BP5	Not met	The CDH1 VCEP applies BP5 when a pathogenic/likely pathogenic variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1). No such data are available for this case.
BP6	N/A	BP6 is designated as Not Applicable for this VCEP (ClinGen CDH1 Expert Panel Specifications Version 3.1). Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	Under the CDH1 VCEP, BP7 applies only to synonymous and intronic variants at or beyond +7 to -21 locations. NM_004360.5:c.2077G>A is a missense variant and does not qualify.	cspec

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