Variant: NM_004360.5(CDH1):c.1008+2T>C

CA16615376

406652 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 24d1a63e-11db-4d0c-85c0-5d1e6efcbcf0

Approved on: 2023-08-24

Published on: 2023-08-24

HGVS expressions

NM_004360.5:c.1008+2T>C
NM_004360.5(CDH1):c.1008+2T>C
NC_000016.10:g.68811861T>C
CM000678.2:g.68811861T>C
NC_000016.9:g.68845764T>C
CM000678.1:g.68845764T>C
NC_000016.8:g.67403265T>C
NG_008021.1:g.79570T>C
ENST00000261769.10:c.1008+2T>C
ENST00000261769.9:c.1008+2T>C
ENST00000422392.6:c.1008+2T>C
ENST00000561751.1:n.630+2T>C
ENST00000562836.5:n.1079+2T>C
ENST00000566510.5:c.852+2T>C
ENST00000566612.5:c.1008+2T>C
ENST00000611625.4:c.1008+2T>C
ENST00000612417.4:c.1008+2T>C
ENST00000621016.4:c.1008+2T>C
NM_004360.3:c.1008+2T>C
NM_001317184.1:c.1008+2T>C
NM_001317185.1:c.-608+2T>C
NM_001317186.1:c.-812+2T>C
NM_004360.4:c.1008+2T>C
NM_001317184.2:c.1008+2T>C
NM_001317185.2:c.-608+2T>C
NM_001317186.2:c.-812+2T>C

Likely Pathogenic

• Met criteria codes: PVS1_Strong PS4_Supporting PM2_Supporting PM5_Supporting

• Not Met criteria codes: BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS3 PS1 PP4 PP1 PP3 PP2 PM3 PM1 PM4 PM6 BA1

Expert Panel

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.1008+2T>C variant occurs at the canonical splice donor site of exon 7 and is predicted to result in a truncated or absent protein (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org/). In addition, this variant has been identified in one family meeting IGCLC criteria for HDGC (PS4_supporting; SCV000545440.4). Although functional studies have not been reported for this variant, CDH1 c.1008G>T (p.Glu336Asp), affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing (PMID: 31642931). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting.

Met criteria codes

• PVS1_Strong: This variant occurs at the canonical splice donor site of exon 7.
• PS4_Supporting: One family meets IGCLC criteria for HDGC (SCV000545440.4).
• PM2_Supporting: This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.
• PM5_Supporting: Apply PM5_Supporting to the variant with the alteration at canonical splicing site.

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: To our knowledge, segregation of this variant has not been reported.
• BS3: To our knowledge, in vitro splicing analysis for this variant has not been reported.
• BS1: This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.
• BP2: To our knowledge, this variant has not been observed in cis or trans with a known pathogenic variant.
• BP3: BP3 does not apply to CDH1.
• BP4: BP4 does not apply to this variant.
• BP1: BP1 does not apply to CDH1.
• BP5: To our knowledge, this variant has not been found in a case with an alternate molecular basis for disease.
• BP7: BP7 does not apply to this variant.
• PS2: To our knowledge, this variant has not been reported as de novo.
• PS3: To our knowledge, in vitro splicing analysis for this variant has not been reported. The CDH1 c.1008G>T variant, affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing (PMID: 31642931).
• PS1: PS1 does not apply to this variant.
• PP4: PP4 does not apply to CDH1.
• PP1: Need more information about the pedigree of the family (SCV000545440.4)
• PP3: PP3 does not apply to this variant.
• PP2: PP2 does not apply to CDH1.
• PM3: PM3 does not apply to CDH1.
• PM1: PM1 does not apply to CDH1.
• PM4: PM4 does not apply to this variant.
• PM6: To our knowledge, this variant has not been reported as de novo.
• BA1: This variant is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP.