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]

Variant: NM_004360.4(CDH1):c.33G>C (p.Leu11=)

CA298941

182377 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1f318c7a-27f7-45cf-93c7-a000171e164e
Approved on: 2023-08-17
Published on: 2023-08-17

HGVS expressions

NM_004360.4:c.33G>C
NM_004360.4(CDH1):c.33G>C (p.Leu11=)
NC_000016.10:g.68737448G>C
CM000678.2:g.68737448G>C
NC_000016.9:g.68771351G>C
CM000678.1:g.68771351G>C
NC_000016.8:g.67328852G>C
NG_008021.1:g.5157G>C
ENST00000261769.10:c.33G>C
ENST00000261769.9:c.33G>C
ENST00000422392.6:c.33G>C
ENST00000566510.5:c.33G>C
ENST00000566612.5:c.33G>C
ENST00000611625.4:c.33G>C
ENST00000612417.4:c.33G>C
ENST00000621016.4:c.33G>C
NM_004360.3:c.33G>C
NM_001317184.1:c.33G>C
NM_001317185.1:c.-1583G>C
NM_001317186.1:c.-1787G>C
NM_004360.5:c.33G>C
NM_001317184.2:c.33G>C
NM_001317185.2:c.-1583G>C
NM_001317186.2:c.-1787G>C
NM_004360.5(CDH1):c.33G>C (p.Leu11=)
More

Likely Benign

Met criteria codes 3
BS2 BP7 BP4
Not Met criteria codes 23
PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PP2 PM6 PM2 PM4 PM3 PM1 PM5 PVS1 BS4 BS3 BS1 BP5 BP3 BP2 BP1

Evidence Links 0

Expert Panel

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.33G>C (p.Leu11=) variant results in a synonymous amino acid variant within exon 1. This variant is present at an allele frequency of 0.00012 (18/153328) in gnomAD, with a maximum frequency of 0.00026 (16/60398) in the European (Non-Finnish) subpopulation (http://gnomad.broadinstitute.org). The variant has been observed in more than 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2). This variant occurs at a nucleotide that is not highly conserved across species and it is not predicted to alter splicing by multiple splice site predictors (BP7, BP4). Although one predictor suggests alteration of an exonic ESE site, the impact of these events has not been well-characterized experimentally. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4, BP7.
Met criteria codes
BS2
This variant has been identified in more than 70 individuals with clinical multigene panel sequencing but with uncharacterized phenotypes (SCV000210878.10). Three of these individuals had pathogenic variants in other cancer predisposition genes but who had overlapping clinical phenotypes. The variant has been identified in an additional 21 individuals, 20 with available clinical data but none who meet IGCLC criteria (SCV000213221.4).
BP7
This nucleotide is not highly conserved across species.
BP4
This variant is not predicted to alter splicing by multiple splice site predictors. The variant is predicted by HumanSpliceFinder to alter an exonic ESE site; however, the impact of these events has not been well-characterized.
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
Not applicable.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Not applicable.
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
Not applicable.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
Not applicable.
PM3
Not applicable.
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Not applicable.
PVS1
Not applicable.
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
BS1
This variant is present at an allele frequency of 0.00012 (18/153328) in gnomAD, with a maximum frequency 0.00026 (16/60398) in the European (Non-Finnish) subpopulation.
BP5
This variant has been observed in at least three individuals with a personal and/or family history of breast, gastric and/or other cancer and with pathogenic/likely pathogenic variants in cancer predisposition genes associated with other syndromes that might explain the phenotype (SCV000210878.10). But BP5 only applies if a P/LP variant is identified in an alternate gene known to cause HDGC (e.g., CTNNA1).
BP3
Not applicable.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Not applicable.
Curation History
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