Variant: NM_004360.5(CDH1):c.32_34TGC[7] (p.Leu14_Leu15dup)

142455 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 32a09493-4519-46f6-b57a-e60d03a9272e

Approved on: 2023-08-18

Published on: 2023-08-18

HGVS expressions

NM_004360.5:c.32_34TGC[7]
NM_004360.5(CDH1):c.32_34TGC[7] (p.Leu14_Leu15dup)
NM_004360.5(CDH1):c.32TGC[7] (p.Leu14_Leu15dup)

Likely Benign

• Met criteria codes: BS2 PM2_Supporting

• Not Met criteria codes: PM6 PM3 PM5 PM1 PM4 BA1 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS4 PS1 PS3 PP4 PP1 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.32_34TGC[7] (p.Leu14_Leu15dup) variant results in an in-frame insertion in exon 1. This variant has a frequency of 0.0008% in gnomAD (1 of 124,448) (PM2_Supporting; https://gnomad.broadinstitute.org/). However, this region has poor coverage and allele frequency estimates may not be reliable. This variant has also been identified in at least ten individuals without DGC, SRC tumours and LBC and whose families do not suggest HDGC (BS2, SCV000569203.4, SCV000186596.5, SCV000545430.4). In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, PM2_Supporting.

Met criteria codes

• BS2: This variant was identified in 21 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (SCV000569203.4, SCV000186596.5, SCV000545430.4). Note that 4 individuals reported gastric cancer (unknown histology) or lobular breast cancer in their family, but whose families are not otherwise suggestive of HDGC. Therefore, this variant meets criteria for BS2 based on at least 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC.
• PM2_Supporting: This variant was identified in 1 of 124,448 alleles in gnomAD. Note that this variant is covered in fewer than 50% of individuals in gnomAD v2.1.1 exomes and allele frequency estimates may not be reliable.

Not Met criteria codes

• PM6: To our knowledge, this variant has not been reported as de novo.
• PM3: PM3 does not apply to CDH1.
• PM5: PM5 does not apply to CDH1.
• PM1: PM1 does not apply to CDH1.
• PM4: This variant results in the insertion of two leucine molecules in a short repeat region encoding a string of five leucines in the signal peptide region (exon 1). Therefore, the effect of this variant on protein function is uncertain.
• BA1: This variant was identified in 1 of 124,448 alleles in gnomAD. Note that this variant is covered in fewer than 50% of individuals in gnomAD v2.1.1 exomes and allele frequency estimates may not be reliable.
• BS4: To our knowledge, segregation of this variant has not been reported.
• BS3: BS3 does not apply to this variant.
• BS1: This variant was identified in 1 of 124,448 alleles in gnomAD. Note that this variant is covered in fewer than 50% of individuals in gnomAD v2.1.1 exomes and allele frequency estimates may not be reliable.
• BP5: To our knowledge, this variant has not been identified in a case with an alternate molecular basis for disease.
• BP7: BP7 does not apply to this variant.
• BP2: To our knowledge, this variant has not been reported 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.
• PVS1: PVS1 does not apply to this variant.
• PS2: To our knowledge, this variant has not been reported as de novo.
• PS4: This variant was identified in 21 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (SCV000569203.4, SCV000186596.5, SCV000545430.4). Note that 4 individuals reported gastric cancer (unknown histology) or lobular breast cancer in their family, but whose families are not otherwise suggestive of HDGC. Therefore, this variant meets criteria for BS2 based on at least 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC.
• PS1: PS1 does not apply to this variant.
• PS3: PS3 does not apply to this variant.
• PP4: PP4 does not apply to CDH1.
• PP1: To our knowledge, segregation of this variant has not been reported.
• PP3: PP3 does not apply to this variant.
• PP2: PP2 does not apply to CDH1.