Variant: NM_004360.5(CDH1):c.1711+5G>A

CA645369681

428630 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 9293f90f-235f-432c-8bea-74566414c9d9

HGVS expressions

NM_004360.5:c.1711+5G>A
NM_004360.5(CDH1):c.1711+5G>A
NC_000016.10:g.68819430G>A
CM000678.2:g.68819430G>A
NC_000016.9:g.68853333G>A
CM000678.1:g.68853333G>A
NC_000016.8:g.67410834G>A
NG_008021.1:g.87139G>A
ENST00000261769.10:c.1711+5G>A
ENST00000261769.9:c.1711+5G>A
ENST00000422392.6:c.1528+5G>A
ENST00000562836.5:n.1782+5G>A
ENST00000566510.5:c.*377+5G>A
ENST00000566612.5:c.1566-2571G>A
ENST00000611625.4:c.1774+5G>A
ENST00000612417.4:c.1711+5G>A
ENST00000621016.4:c.1711+5G>A
NM_004360.3:c.1711+5G>A
NM_001317184.1:c.1528+5G>A
NM_001317185.1:c.163+5G>A
NM_001317186.1:c.-254-2571G>A
NM_004360.4:c.1711+5G>A
NM_001317184.2:c.1528+5G>A
NM_001317185.2:c.163+5G>A
NM_001317186.2:c.-254-2571G>A

Uncertain Significance

• Met criteria codes: PS4_Moderate PS3_Supporting PM2_Supporting

• Not Met criteria codes: PM3 PM1 PM4 BS1 BS2 BP7 BP3 BP4 BP1 PS1 BA1 PP4 PP3 PP2

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

Evidence submitted by expert panel

CDH1 VCEP

The c.1711+5G>A variant in CDH1 is an intronic variant which switches a G to an A in the +5 position of intron 11. This variant is known in five families, three of which meet HDGC criteria (PS4_moderate; PMID: 15235021, AmbryGenetics, Invitae, Color and CeTaG internal data). This variant is completely absent from population databases such as gnomAD (PM2_supporting). There is evidence of abnormal RNA expression of this variant allele as a functional consequence of incorrect slicing, but further studies are required to confirm this evidence (PS3_supporting; PMID: 15235021). In summary, this variant is classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen CDH1 Variant Curation Expert Panel: PS3_supporting, PS4_moderate, PM2_supporting. (CDH1 VCEP specifications version 3.1; 06/26/2023)

Met criteria codes

• PS4_Moderate: This variant has been reported in 3 families meeting HDGC criteria (PS4_Moderate); PMID: 15235021, Ambry, Invitae).
• PS3_Supporting: RT-PCR of cDNA demonstrated that the variant impacts splicing by skipping the out-of-frame exon 11 (PMID: 15235021) (PS3_supporting).
• PM2_Supporting: This variant is absent from gnomAD v3.1.2 (PM2_Supporting)

Not Met criteria codes

• PM3: Not applicable
• PM1: Not applicable
• PM4: Not applicable
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: This variant has been observed in 2 heterozygous individuals with no diffuse gastric cancer, signet ring cell carcinoma or lobular breast cancer and/or whose family histories do not suggest HDGC (Color; CeGaT).
• BP7: Not applicable
• BP3: Not applicable
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: Not applicable
• 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
• PP3: The results from 3 in silico splicing predictors SpliceAI, MaxEntScan and NetGene indicate that this variant does not affect splicing.
• PP2: Not applicable

Approved on: 2023-08-03

Published on: 2023-08-03