Variant: NM_004360.4(CDH1):c.504delA (p.Gly169Alafs)

CA348941

220776 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 47cfd75c-4c6e-4e49-a686-94e05a7c43db

Approved on: 2023-08-25

Published on: 2023-08-25

HGVS expressions

NM_004360.4:c.504del
NM_004360.4(CDH1):c.504delA (p.Gly169Alafs)
NC_000016.10:g.68808540del
CM000678.2:g.68808540del
NC_000016.9:g.68842443del
CM000678.1:g.68842443del
NC_000016.8:g.67399944del
NG_008021.1:g.76249del
ENST00000261769.10:c.504del
ENST00000261769.9:c.504del
ENST00000422392.6:c.504del
ENST00000561751.1:n.271del
ENST00000562836.5:n.575del
ENST00000564676.5:n.786del
ENST00000564745.1:n.499del
ENST00000566510.5:c.504del
ENST00000566612.5:c.504del
ENST00000567320.1:n.14del
ENST00000611625.4:c.504del
ENST00000612417.4:c.504del
ENST00000621016.4:c.504del
NM_004360.3:c.504del
NM_001317184.1:c.504del
NM_001317185.1:c.-1112del
NM_001317186.1:c.-1316del
NM_004360.5:c.504del
NM_001317184.2:c.504del
NM_001317185.2:c.-1112del
NM_001317186.2:c.-1316del
NM_004360.5(CDH1):c.504del (p.Gly169fs)

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PS4_Supporting PM5_Supporting

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

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.504delA p.(Gly169Alafs) 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 one family meeting HDGC clinical criteria (PS4_Supporting; DOI: 10.1200/PO.16.00021). 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_Supporting, PM5_Supporting.

Met criteria codes

• PM2_Supporting: Absent in population databases.
• PVS1: Exon 4 of 16. Predicted NMD.
• PS4_Supporting: DOI: 10.1200/PO.16.00021 (Lowstuter et al, JCO Precision Oncology - published online March 29, 2017) - one 44yo individual with ILC (initial path: ductal but re-classified to lobular due to absence of CDH1 expression in tumour). Reported to fulfill the IGCLC criteria (2010 and 2015). 4 family members with gastric cancer (no pathology provided).
• PM5_Supporting: Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.

Not Met criteria codes

• PM6: 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
• PM1: 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
• BS2: 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
• BS4: 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
• 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
• BP2: 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
• BP5: 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
• PS3: 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline