Variant: NM_001317186.2:c.-403G>A

CA288037

127914 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 83921f5d-95da-4bbf-9dbe-4afe1c1ec6e6

HGVS expressions

NM_001317186.2:c.-403G>A
NC_000016.10:g.68815611G>A
CM000678.2:g.68815611G>A
NC_000016.9:g.68849514G>A
CM000678.1:g.68849514G>A
NC_000016.8:g.67407015G>A
NG_008021.1:g.83320G>A
ENST00000261769.10:c.1417G>A
ENST00000261769.9:c.1417G>A
ENST00000422392.6:c.1234G>A
ENST00000562836.5:n.1488G>A
ENST00000566510.5:c.*83G>A
ENST00000566612.5:c.1417G>A
ENST00000611625.4:c.1480G>A
ENST00000612417.4:c.1417G>A
ENST00000621016.4:c.1417G>A
NM_004360.3:c.1417G>A
NM_001317184.1:c.1234G>A
NM_001317185.1:c.-132G>A
NM_001317186.1:c.-403G>A
NM_004360.4:c.1417G>A
NM_004360.5:c.1417G>A
NM_001317184.2:c.1234G>A
NM_001317185.2:c.-132G>A
NM_004360.5(CDH1):c.1417G>A (p.Val473Ile)

Likely Benign

• Met criteria codes: BS2

• Not Met criteria codes: BA1 PS2 PS3 PS4 PP1 PP3 PM6 PM2 BS4 BS3 BS1 BP5 BP2

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.1417G>A (p.Val473Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 5 of 152,172 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023)

Met criteria codes

• BS2: This variant has been observed in ~383 families without HDGC. This variant was also identified in two families with a history of unspecified gastric and gastrointestinal cancer and two probands with ILC in 60s.

Not Met criteria codes

• BA1: This variant occurs at a frequency of 3.3x10-5 (5 in 152,172 alleles) in gnomAD.
• PS2: To our knowledge, this variant has not been reported in a proband with HDGC.
• PS3: To our knowledge, splicing studies have not been reported for this variant.
• PS4: This variant has been observed in ~383 families without HDGC. This variant was also identified in two families with a history of unspecified gastric and gastrointestinal cancer and two probands with ILC in 60s.
• PP1: To our knowledge, this variant has not been reported in a family meeting IGCLC criteria for HDGC.
• PP3: This variant is not predicted to result in abnormal splicing.
• PM6: To our knowledge, this variant has not been reported in a proband with HDGC.
• PM2: This variant occurs at a frequency of 3.3x10-5 (5 in 152,172 alleles) in gnomAD.
• BS4: To our knowledge, this variant has not been reported in a family meeting IGCLC criteria for HDGC.
• BS3: To our knowledge, splicing studies have not been reported for this variant.
• BS1: This variant occurs at a frequency of 3.3x10-5 (5 in 152,172 alleles) in gnomAD.
• BP5: To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.
• BP2: To our knowledge, this variant has not been reported in a family meeting IGCLC criteria for HDGC.

Approved on: 2023-08-03

Published on: 2023-08-03