NM_004360.5:c.1239C>T

CDH1 · NP_004351.1:p.(Tyr413=) · NM_004360.5

GRCh37: chr16:68847317 C>T · GRCh38: chr16:68813414 C>T

Gene: CDH1 Transcript: NM_004360.5

Final call

Likely Benign

BS1 strong BP2 supporting BP7 supporting

Variant details

Gene

CDH1

Transcript

NM_004360.5

Protein

NP_004351.1:p.(Tyr413=)

gnomAD AF

9.293012398117608e-05 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The CDH1 NM_004360.5:c.1239C>T (p.Tyr413=, p.Y413=) variant has not been observed in COSMIC and has been reported in ClinVar predominantly as benign or likely benign.

This variant is present in gnomAD above the CDH1 BS1 threshold of 0.1%, reaching 0.11215% in African/African American individuals in gnomAD v2.1 and 0.16258% in African/African American individuals in gnomAD v4.1, but it remains below the BA1 threshold of 0.2%.

In gnomAD v4.1, this variant is also observed in the homozygous state in 3 individuals, supporting BP2 under the CDH1 specification.

In silico splicing evidence does not support a splice-altering effect, with SpliceAI showing a maximum delta score of 0.01, which is consistent with applying BP7 for this synonymous internal exonic variant and does not support PP3.

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 synonymous CDH1 variant does not fall into the CDH1 or generic PVS1 null-variant categories, and available evidence does not support loss of function through a canonical splice-site mechanism.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	PS1 is not applicable in the CDH1 specification.	cspec
PS2	Not assessed	No de novo data with parental confirmation were identified for this variant.	cspec clinvar
PS3	Not assessed	No RNA assay demonstrating an abnormal CDH1 transcript was identified for this variant.	cspec clinvar oncokb
PS4	Not assessed	Available evidence does not document the number of families meeting CDH1 hereditary diffuse gastric cancer criteria for this variant.	cspec clinvar
PM1	N/A	PM1 is not applicable in the CDH1 specification.	cspec hotspots
PM2	Not met	This variant does not meet the CDH1 PM2_Supporting rarity threshold because it is present above 1 in 100,000 alleles overall and above 1 in 50,000 alleles in the African/African American population in both gnomAD v2.1 and v4.1.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the CDH1 specification.	cspec
PM4	N/A	PM4 is restricted to stop-loss variants in the CDH1 specification, and this variant is synonymous.	cspec
PM5	N/A	PM5 is repurposed in the CDH1 specification for truncating-variant logic and is not applicable to this synonymous variant.	cspec pm5_candidates
PM6	Not assessed	No de novo occurrence without parental confirmation was identified for this variant.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant.	cspec clinvar
PP2	N/A	PP2 is not applicable in the CDH1 specification.	cspec
PP3	Not met	Available computational evidence does not support an adverse splicing effect. SpliceAI shows a maximum delta score of 0.01, and the evidence reviewed does not document at least three concordant splicing predictors as required for CDH1 PP3.	cspec spliceai
PP4	N/A	PP4 is not applicable in the CDH1 specification.	cspec
PP5	N/A	PP5 is not applicable in the CDH1 specification.	cspec
BA1	Not met	This variant does not reach the CDH1 BA1 stand-alone frequency threshold of 0.2%. The highest observed population frequency is 0.16258% in African/African American individuals in gnomAD v4.1, which is below the 0.2% cutoff.	cspec gnomad_v4 gnomad_v2
BS1	Met	Population frequency exceeds the CDH1 BS1 threshold of 0.1%. The highest observed frequency is 0.11215% in gnomAD v2.1 African/African American individuals and 0.16258% in gnomAD v4.1 African/African American individuals, both above the 0.1% cutoff.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Although this variant is present in population databases, no dataset was identified showing the required number of individuals without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer and without family histories suggestive of HDGC.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	No functional RNA study demonstrating no impact on CDH1 transcript composition was identified for this variant.	cspec clinvar oncokb
BS4	Not assessed	No segregation data showing lack of segregation with disease were identified.	cspec clinvar
BP1	N/A	BP1 is not applicable in the CDH1 specification.	cspec
BP2	Met	This variant is observed in the homozygous state in gnomAD, which meets the CDH1 BP2 supporting rule. In gnomAD v4.1, 3 homozygotes are reported, all in the African/African American population.	cspec gnomad_v4
BP3	N/A	BP3 is not applicable in the CDH1 specification.	cspec
BP4	Not met	Splicing prediction does not show a significant effect, with a SpliceAI maximum delta score of 0.01, but the evidence reviewed does not document the at least three concordant splicing predictors required for CDH1 BP4.	cspec spliceai
BP5	Not assessed	No alternate molecular explanation was identified that would support BP5 for this variant.	cspec clinvar
BP6	N/A	BP6 is not applicable in the CDH1 specification.	cspec
BP7	Met	This is a synonymous variant, NM_004360.5:c.1239C>T (p.Tyr413=), located well within exon 9 rather than near the splice junction, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. This meets the CDH1 BP7 rule for synonymous variants outside the specified splice-region window.	cspec spliceai

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