Variant: NM_004360.5(CDH1):c.369_375CCGCCCC[3] (p.His128fs)

567576 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: f95f187d-ae7b-4e38-8df0-a1bc2fdeb7cb

Approved on: 2023-08-04

Published on: 2023-08-04

HGVS expressions

NM_004360.5:c.369_375CCGCCCC[3]
NM_004360.5(CDH1):c.369_375CCGCCCC[3] (p.His128fs)
NM_004360.5(CDH1):c.376_382dup (p.His128fs)

Pathogenic

• Met criteria codes: PM2_Supporting PM5_Supporting PVS1

• Not Met criteria codes: PM6 PM3 PM1 PM4 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

Evidence submitted by expert panel

CDH1 VCEP

The c.369_375CCGCCCC[3] (p.His128Profs*42) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD.
• PM5_Supporting: This variant occurs in exon 3 and is predicted to result in a premature stop codon that leads to NMD.
• PVS1: This variant occurs in exon 3 and is predicted to result in a premature stop codon that leads to a truncated or absent protein.

Not Met criteria codes

• PM6: To our knowledge, this variant has not been reported as de novo.
• PM3: PM3 does not apply to CDH1.
• PM1: PM1 does not apply to CDH1.
• PM4: PM4 does not apply to frameshift variants.
• BA1: This variant is absent from gnomAD.
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: BS3 only applies to variants predicted to affect splicing.
• BS1: This variant is absent from gnomAD.
• BP2: To our knowledge, this variant has not been reported in cis or trans with a pathogenic variant.
• BP3: BP3 does not apply to CDH1.
• BP4: BP4 does not apply to frameshift variants.
• BP1: BP1 does not apply to CDH1.
• BP5: To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.
• BP7: BP7 does not apply to frameshift variants.
• PS2: To our knowledge, this variant has not been reported as de novo.
• PS4: SCV000815290.1 - This family does not meet IGCLC criteria for HDGC so at this time PS4 cannot be applied.
• PS3: PS3 only applies to variants predicted to affect splicing.
• PS1: PS1 does not apply to this variant.
• PP4: PP4 does not apply to CDH1.
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: PP3 does not apply to frameshift variants.
• PP2: PP2 does not apply to CDH1.