Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

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

CA658658491

449339 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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

PVS1 PM2_Supporting PS4_Supporting PM5_Supporting

BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS3 PS1 BA1 PP4 PP3 PP2 PP1 PM3 PM1 PM4 PM6

Evidence Links 0

Expert Panel

CDH1 VCEP

Criteria Specification Information

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

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, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting.

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_Supporting

Variant not present in gnomAD

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)

PM5_Supporting

Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.

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

Variant not present in gnomAD

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP3

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

BP1

variant is predicted to result in a premature stop codon that leads to a truncated or absent protein

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

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

variant is predicted to result in a premature stop codon that leads to a truncated or absent protein

BA1

Variant not present in gnomAD

PP4

Use PS4 in place of PP4

PP3

variant is predicted to result in a premature stop codon that leads to a truncated or absent protein

PP2

variant is predicted to result in a premature stop codon that leads to a truncated or absent protein

PP1

applied PS4 instead; sequencing confirmed presence of the variant in 3 affected individuals (proband, mother, maternal aunt) in one family (PMID: 10477433)

PM3

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

PM4

variant is predicted to result in a premature stop codon that leads to a truncated or absent protein

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-08-25

Published on: 2023-08-25

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