Variant: NM_004360.4(CDH1):c.1895_1896delAC (p.His632Argfs)

406628 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 65458bc2-ea32-41ce-87e1-c4fc4183acdc

Approved on: 2023-08-25

Published on: 2023-08-25

HGVS expressions

NM_004360.4:c.1895_1896del
NM_004360.4(CDH1):c.1895_1896delAC (p.His632Argfs)
NM_004360.5(CDH1):c.1895_1896del (p.His632fs)

Pathogenic

• Met criteria codes: PM5_Supporting PM2_Supporting PS4_Moderate PVS1

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

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.1895_1896delAC (p.His632ArgfsTer30) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two familes meeting HDGC clinical criteria (PS4_Moderate; PMID 26182300, https://doi.org/10.2147/GICTT.S16330). In summary, 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting.

Met criteria codes

• PM5_Supporting: Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.
• PM2_Supporting: Absent in gnomAD
• PS4_Moderate: At least 2 families meeting HDGC clinical criteria (PMID: 26182300, Shenoy et al. 2011 - https://doi.org/10.2147/GICTT.S16330: extensive FH of gastric cancer, and case diagnosed with LBC and in situ SRC carcinoma detected in path specimen of gastrectomy).
• PVS1: A 2 bp deletion in exon 12/16, predicted to result in a truncated or absent protein

Not Met criteria codes

• BA1: 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: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: Shenoy et al. 2011 - https://doi.org/10.2147/GICTT.S16330: two affected segregations, and apparent incomplete penetrance
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline