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

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

CA16620223

419385 (ClinVar)

Gene: CDH1
Condition: hereditary diffuse gastric cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 30836981-bd2f-4569-aa8e-e0916d43c904
Approved on: 2019-07-18
Published on: 2019-09-11

HGVS expressions

NM_004360.4:c.-49_-48insGCCCG
NM_004360.4(CDH1):c.-49_-48insGCCCG
NC_000016.10:g.68737363_68737367dup
CM000678.2:g.68737363_68737367dup
NC_000016.9:g.68771266_68771270dup
CM000678.1:g.68771266_68771270dup
NC_000016.8:g.67328767_67328771dup
NG_008021.1:g.5072_5076dup
ENST00000261769.10:c.-53_-49dup
ENST00000261769.9:c.-53_-49dup
ENST00000422392.6:c.-53_-49dup
ENST00000566510.5:c.-53_-49dup
ENST00000566612.5:c.-53_-49dup
ENST00000611625.4:c.-53_-49dup
ENST00000612417.4:c.-53_-49dup
ENST00000621016.4:c.-53_-49dup
NM_004360.3:c.-53_-49dup
NM_001317184.1:c.-53_-49dup
NM_001317185.1:c.-1668_-1664dup
NM_001317186.1:c.-1872_-1868dup
NM_004360.4:c.-53_-49dup
NM_004360.5:c.-53_-49dup
NM_001317184.2:c.-53_-49dup
NM_001317185.2:c.-1668_-1664dup
NM_001317186.2:c.-1872_-1868dup
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Uncertain Significance

Met criteria codes 1
PM2
Not Met criteria codes 25
PM6 PM1 PM3 PM5 PM4 PVS1 BA1 BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 PS1 PS2 PS3 PS4 PP1 PP2 PP3 PP4

Evidence Links 1

Expert Panel

Criteria Specification Information

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; 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: PM2.
Met criteria codes
PM2
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.
Not Met criteria codes
PM6
To our knowledge, this variant has not been reported as de novo.
PM1
This rule does not apply to CDH1.
PM3
This rule is not applicable for CDH1.
PM5
This rule does not apply to this variant.
PM4
This rule does not apply to this variant.
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).
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.
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.
PubMed:23431106
BP4
This rule does not apply to this variant.
BP3
This rule does not apply to CDH1.
BP1
This rule does not apply to CDH1.
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.
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.
PS1
This rule does not apply to this variant.
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).
PubMed:23431106
PS4
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).
PP1
To our knowledge, segregation data has not been reported for this variant.
PP2
This rule does not apply to CDH1.
PP3
This rule does not apply to this variant.
PP4
Not applicable.
Curation History
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