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_004360.3(CDH1):c.521dupA (p.Asn174Lysfs)

CA163603

140803 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
UUID: 7f7ae9a1-f6ed-4488-abe5-18ab7289bf2b
Approved on: 2023-08-25
Published on: 2023-08-25

HGVS expressions

NM_004360.3:c.521dupA
NM_004360.3(CDH1):c.521dupA (p.Asn174Lysfs)
NC_000016.10:g.68808557dup
CM000678.2:g.68808557dup
NC_000016.9:g.68842460dup
CM000678.1:g.68842460dup
NC_000016.8:g.67399961dup
NG_008021.1:g.76266dup
ENST00000261769.10:c.521dup
ENST00000261769.9:c.521dup
ENST00000422392.6:c.521dup
ENST00000561751.1:n.288dup
ENST00000562836.5:n.592dup
ENST00000564676.5:n.803dup
ENST00000564745.1:n.516dup
ENST00000566510.5:c.521dup
ENST00000566612.5:c.521dup
ENST00000567320.1:n.31dup
ENST00000611625.4:c.521dup
ENST00000612417.4:c.521dup
ENST00000621016.4:c.521dup
NM_004360.3:c.521dup
NM_001317184.1:c.521dup
NM_001317185.1:c.-1095dup
NM_001317186.1:c.-1299dup
NM_004360.4:c.521dup
NM_004360.5:c.521dup
NM_001317184.2:c.521dup
NM_001317185.2:c.-1095dup
NM_001317186.2:c.-1299dup
NM_004360.5(CDH1):c.521dup (p.Asn174fs)
More

Pathogenic

Met criteria codes 4
PS4_Moderate PM2_Supporting PVS1 PM5_Supporting
Not Met criteria codes 22
BS3 BS4 BS1 BS2 BP7 BP5 BP3 BP4 BP1 BP2 PS1 PS3 PS2 BA1 PP3 PP2 PP4 PP1 PM4 PM1 PM3 PM6

Evidence Links 4

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.521dupA p.(Asn174Lysfs) 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://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17660459 and doi:10.1200/PO.16.00021). Therefore, 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_Moderate, PM5_Supporting.
Met criteria codes
PS4_Moderate
PMID: 17660459 - 2 LBC under 50 yo (variant published as 517insA). DOI: 10.1200/PO.16.00021 (Lowstuter et al, Unexpected CDH1 mutations identified on multi-gene panels pose clinical management challenges. J Precis Oncol doi:10.1200/PO.16.00021) - One proband with signet cell gastric cancer.

PM2_Supporting
Absent in population databases.
PVS1
Exon 4 of 16. Predicted NMD.
PM5_Supporting
Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.
Not Met criteria codes
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
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
BP5
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
BP2
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
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
BA1
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
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
PP1
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
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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