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]
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Variant: NM_004360.4(CDH1):c.1565+2dupT

CA16614980

406624 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f3284e5b-5df2-4a09-a584-cef2afeff39a
Approved on: 2023-08-30
Published on: 2023-08-30

HGVS expressions

NM_004360.4:c.1565+2dup
NM_004360.4(CDH1):c.1565+2dupT
NC_000016.10:g.68815761dup
CM000678.2:g.68815761dup
NC_000016.9:g.68849664dup
CM000678.1:g.68849664dup
NC_000016.8:g.67407165dup
NG_008021.1:g.83470dup
ENST00000261769.10:c.1565+2dup
ENST00000261769.9:c.1565+2dup
ENST00000422392.6:c.1382+2dup
ENST00000562836.5:n.1636+2dup
ENST00000566510.5:c.*231+2dup
ENST00000566612.5:c.1565+2dup
ENST00000611625.4:c.1628+2dup
ENST00000612417.4:c.1565+2dup
ENST00000621016.4:c.1565+2dup
NM_004360.3:c.1565+2dup
NM_001317184.1:c.1382+2dup
NM_001317185.1:c.17+2dup
NM_001317186.1:c.-255+2dup
NM_004360.5:c.1565+2dup
NM_001317184.2:c.1382+2dup
NM_001317185.2:c.17+2dup
NM_001317186.2:c.-255+2dup
NM_004360.5(CDH1):c.1565+2dup

Pathogenic

Met criteria codes 6
PS4 PP1_Moderate PVS1_Strong PP3_Moderate PM2_Supporting PM5_Supporting
Not Met criteria codes 20
PS3 PS2 PS1 BA1 PP4 PP2 PM6 PM1 PM3 PM4 BS2 BS3 BS4 BS1 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 6

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.1565+2dupT variant is a intronic variant in the donor region of intron 10 (PVS1_Strong, PM5_Supporting). This variant affects the same splice site as a well-characterized splice variant with similar or worse in silico/RNA predictions (PP3_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). It has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID: 18391748, 23709761, 25315765, 26072394, SCV000665426.2), and was also found to co-segregate with disease in multiple affected family members with 5 meioses observed (PP1_Moderate; PMID: 25315765, 22020549, SCV000665426.2). 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_Strong, PS4, PM2_Supporting, PM5_Supporting, PP1_Moderate, PP3_Moderate.
Met criteria codes
PS4
Six families that meet HDGC clinical criteria (PMID: 18391748, 23709761, 25315765, 26072394, SCV000665426.2). Three families that do not meet HDGC clinical criteria due to lack of information (SCV000665426.2)
One Dutch family that meets HDGC clinical criteria, which is also reported in van der Post et al. 2015 PubMed:22020549
Based on supplementary data it appears that the family from Rogers et al. 2008 is included in this publication. PubMed:26182300
One family that meets HDGC clinical criteria. Study indicates that superficial intramucosal signet ring carcinoma, is predominantly located in the proximal one third of the stomach in patients with E-cadherin gene mutations. PubMed:18391748
One French family that meets HDGC clinical criteria PubMed:23709761
Two Dutch families that meet HDGC clinical criteria PubMed:26072394
One family from the US that meets HDGC clinical criteria PubMed:25315765
PP1_Moderate
Five meioses reported in 3 families that meets HDGC criteria (PMID: 25315765, 22020549, SCV000665426.2)
Three meioses across a family that meets HDGC clinical criteria. GC occurred in four family members at ages from 43 to 56. PubMed:22020549
One meiosis across a family that meets HDGC clinical criteria, which includes two sisters with DGC. PubMed:25315765
PVS1_Strong
Variant at canonical splice site.
PP3_Moderate
Loss of wild-type donor splice site predicted by MaxEnt, HSF, and NNSplice. Predictions for this variant are worse than the well-established pathogenic variant c.1565+1G>T that also affects the intron 10 donor site.
PM2_Supporting
Absent in gnomAD
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
Not Met criteria codes
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Two individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (SCV000545387.3).
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
Three meioses across a family that meets HDGC clinical criteria. GC occurred in four family members at ages from 43 to 56. PubMed:22020549
One meiosis across a family that meets HDGC clinical criteria, which includes two sisters with DGC. PubMed:25315765
BS1
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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