Variant: NM_004360.5(CDH1):c.360dup (p.His121fs)

CA10583408

239903 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: e116f274-4c06-47a0-a9a0-fef88440fff9

Approved on: 2023-08-25

Published on: 2023-08-25

HGVS expressions

NM_004360.5:c.360dup
NM_004360.5(CDH1):c.360dup (p.His121fs)
NC_000016.10:g.68801866dup
CM000678.2:g.68801866dup
NC_000016.9:g.68835769dup
CM000678.1:g.68835769dup
NC_000016.8:g.67393270dup
NG_008021.1:g.69575dup
ENST00000261769.10:c.360dup
ENST00000261769.9:c.360dup
ENST00000422392.6:c.360dup
ENST00000561751.1:n.127dup
ENST00000562836.5:n.431dup
ENST00000564676.5:n.642dup
ENST00000564745.1:n.355dup
ENST00000566510.5:c.360dup
ENST00000566612.5:c.360dup
ENST00000611625.4:c.360dup
ENST00000612417.4:c.360dup
ENST00000621016.4:c.360dup
NM_004360.3:c.360dup
NM_001317184.1:c.360dup
NM_001317185.1:c.-1256dup
NM_001317186.1:c.-1460dup
NM_004360.4:c.360dup
NM_001317184.2:c.360dup
NM_001317185.2:c.-1256dup
NM_001317186.2:c.-1460dup

Pathogenic

• Met criteria codes: PS4_Supporting PM5_Supporting PM2_Supporting PVS1

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

Expert Panel

CDH1 VCEP

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.360dupG (p.His121Alafs*47) 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, SCV000288479.2). 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

• PS4_Supporting: This variant was identified in a proband meeting the HDGC criteria (SCV000288479.2).
• PM5_Supporting: Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.
• PM2_Supporting: This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.
• 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

• 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.
• 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.
• PS2: To our knowledge, this variant has not been reported as de novo.
• PS3: PS3 does not apply to frameshift variants.
• PS1: PS1 does not apply to this variant.
• PP4: PP4 does not apply to CDH1.
• PP1: To our knowledge, segregation of this variant has not been reported.
• PP3: PP3 does not apply to frameshift variants.
• PP2: PP2 does not apply to CDH1.
• PM3: PM3 does not apply to CDH1.
• PM1: PM1 does not apply to CDH1.
• PM4: PM4 does not apply to frameshift variants.
• PM6: To our knowledge, this variant has not been reported as de novo.
• BA1: This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.
• BS4: To our knowledge, segregation of this variant has not been reported.
• BS3: BS3 does not apply to frameshift variants.
• BS1: This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline