Variant: NM_004360.5(CDH1):c.1590dup (p.Asn531fs)

CA658658491

449339 (ClinVar)

Gene: CDH1

Condition: hereditary diffuse gastric cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 552d88d5-40c6-4f5f-a451-3c5da270c6db

Approved on: 2020-06-16

Published on: 2020-09-16

HGVS expressions

NM_004360.5:c.1590dup
NM_004360.5(CDH1):c.1590dup (p.Asn531fs)
NC_000016.10:g.68819304dup
CM000678.2:g.68819304dup
NC_000016.9:g.68853207dup
CM000678.1:g.68853207dup
NC_000016.8:g.67410708dup
NG_008021.1:g.87013dup
ENST00000261769.10:c.1590dup
ENST00000261769.9:c.1590dup
ENST00000422392.6:c.1407dup
ENST00000562836.5:n.1661dup
ENST00000566510.5:c.*256dup
ENST00000566612.5:c.1566-2697dup
ENST00000611625.4:c.1653dup
ENST00000612417.4:c.1590dup
ENST00000621016.4:c.1590dup
NM_004360.3:c.1590dup
NM_001317184.1:c.1407dup
NM_001317185.1:c.42dup
NM_001317186.1:c.-254-2697dup
NM_004360.4:c.1590dup
NM_001317184.2:c.1407dup
NM_001317185.2:c.42dup
NM_001317186.2:c.-254-2697dup

Pathogenic

• Met criteria codes: PS4_Supporting PVS1 PM2

• Not Met criteria codes: PP1 PP2 PP3 PP4 BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PM1 PM3 PM5 PM4 PS1 PS2 PS3 BA1 PM6

Expert Panel

Criteria Specification Information

Evidence submitted by expert panel

CDH1 VCEP

The c.1590dup (p.Asn531fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). The variant is absent in the gnomAD cohort (PM2; http://https://gnomad.broadinstitute.org/). This variant has been reported in a family meeting HDGC clinical criteria (PS4_Supporting, PMID: 10477433). 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: PVS1, PM2, PS4_Supporting.

Met criteria codes

• PS4_Supporting: variant identified in a family meeting HDGC clinical criteria (proband and mother with signet cell adenocarcinoma diagnosed at 40 and 48, respectively) (PMID: 10477433)
• PVS1: Duplication results in a frameshift which creates a premature stop codon at position 6 of the new reading frame (position 536 in mutant sequence)
• PM2: Variant not present in gnomAD

Not Met criteria codes

• PP1: applied PS4 instead; sequencing confirmed presence of the variant in 3 affected individuals (proband, mother, maternal aunt) in one family (PMID: 10477433)
• PP2: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• PP3: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• PP4: Use PS4 in place of PP4
• BS1: Variant not present in gnomAD
• 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
• 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: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• BP4: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• BP3: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• BP1: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Do not use for this gene
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• PM4: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• PS1: variant is predicted to result in a premature stop codon that leads to a truncated or absent protein
• 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
• BA1: Variant not present in gnomAD
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline