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]

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Variant: NM_004360.4(CDH1):c.-49_-48insGCCCG

419385 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 30836981-bd2f-4569-aa8e-e0916d43c904

Approved on: 2023-08-21

Published on: 2023-08-21

HGVS expressions

NM_004360.4:c.-49_-48insGCCCG

NM_004360.4(CDH1):c.-49_-48insGCCCG

NM_004360.5(CDH1):c.-58GCCCG[3]

Uncertain Significance

PM2_Supporting

PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS4 PS2 PS3 PS1 PP4 PP1 PP3 PP2 PM3 PM1 PM4 PM5 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.-49_-48insGCCCG variant describes a 5bp insertion in the 5'UTR. The allele is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome hg19. To our knowledge, the c.-49_-48insGCCCG variant has not been reported in the literature. Single nucleotide variants at positions c.-51 and c.-49 have been observed at a low frequency in gnomAD, and the c.-49G>T variant has been reported to slightly increase promoter activity as assessed by luciferase reporter assay (PMID: 23431106). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting.

PM2_Supporting

This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP. Note that the variant occurs in a low complexity region masked by RepeatMasker.

PVS1

This rule does not apply to this variant.

BA1

This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP. Note that the variant occurs in a low complexity region masked by RepeatMasker.

BS2

This variant has been identified in at least two individuals with a personal and family cancer history suggestive of hereditary cancer predisposition but not meeting IGCLC criteria for HDGC due to lack of pathology (SCV000567146.2).

BS4

To our knowledge, segregation data has not been reported for this variant.

BS3

This rule can only be applied to demonstrate splicing defects for CDH1.

BS1

This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP. Note that the variant occurs in a low complexity region masked by RepeatMasker.

BP2

To our knowledge, this variant has not been observed in cis with a pathogenic variant, in trans with a pathogenic variant nor as homozygous in an individual or family without DGC, SRC tumours or LBC.

BP3

This rule does not apply to CDH1.

BP4

This rule does not apply to this variant.

BP1

This rule does not apply to CDH1.

BP5

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

BP7

This rule does not apply to this variant.

PS4

PS2

To our knowledge, this variant has not been reported as de novo.

PS3

This rule can only be applied to demonstrate splicing defects for CDH1. However, the c.-49G>T allele has been associated with slightly higher promoter activity as assessed by luciferase reporter assay (PMID: 23431106).

PS1

This rule does not apply to this variant.

PP4

Not applicable.

PP1

To our knowledge, segregation data has not been reported for this variant.

PP3

This rule does not apply to this variant.

PP2

This rule does not apply to CDH1.

PM3

This rule is not applicable for CDH1.

PM1

This rule does not apply to CDH1.

PM4

This rule does not apply to this variant.

PM5

This rule does not apply to this variant.

PM6

To our knowledge, this variant has not been reported as de novo.

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