Variant: NM_004360.5(CDH1):c.2450C>T (p.Ala817Val)

CA166465

141802 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 9d7dbe5b-ee8e-4a22-8ebe-0cdae8f8b7b0

Approved on: 2023-09-25

Published on: 2023-09-27

HGVS expressions

NM_004360.5:c.2450C>T
NM_004360.5(CDH1):c.2450C>T (p.Ala817Val)
NC_000016.10:g.68833300C>T
CM000678.2:g.68833300C>T
NC_000016.9:g.68867203C>T
CM000678.1:g.68867203C>T
NC_000016.8:g.67424704C>T
NG_008021.1:g.101009C>T
ENST00000261769.10:c.2450C>T
ENST00000261769.9:c.2450C>T
ENST00000422392.6:c.2267C>T
ENST00000562118.1:n.668C>T
ENST00000562836.5:n.2521C>T
ENST00000566510.5:c.*1116C>T
ENST00000566612.5:c.*690C>T
ENST00000611625.4:c.2513C>T
ENST00000612417.4:c.1854-891C>T
ENST00000621016.4:c.1866-903C>T
NM_004360.3:c.2450C>T
NM_001317184.1:c.2267C>T
NM_001317185.1:c.902C>T
NM_001317186.1:c.485C>T
NM_004360.4:c.2450C>T
NM_001317184.2:c.2267C>T
NM_001317185.2:c.902C>T
NM_001317186.2:c.485C>T

Likely Benign

• Met criteria codes: BS2

• Not Met criteria codes: BS1 PM2 PS4 BA1 PP3

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.2450C>T (p.Ala817Val) variant results in a missense change in the last exon of CDH1. This variant is present at a frequency 3.3x10-5 (5 of 152,172 alleles) in the gnomAD population database v3.1.2. This variant has been observed in 104 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In vitro studies of the A817V variant suggest reduced binding of B-catenin and reduced cell aggregation in a HEK293T cell model (PMID: 33929593). However, evaluation of the use of functional data by the VCEP indicates that functional data currently available for missense variants cannot yet predict the pathogenicity of CDH1 variants, and it is therefore not considered in the classification for any CDH1 missense variant (Lee et al, 2018; PMID: 30311375). As such, published information from in vitro or in vivo assays assessing impact on function for this missense variant has not been considered for variant curation. In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2.

Met criteria codes

• BS2: This variant has been identified in more than 104 individuals with DGC, LBC or SRC tumours and whose families do not suggest HDGC. This variant was reported in a family with multiple gliomas and without gastric or lobular breast cancer (PMID: 33929593).

Not Met criteria codes

• BS1: This variant is present at a frequency of 0.00002 (6 of 251,458 alleles) in gnomAD.
• PM2: This variant is present at a frequency of 0.00002 (6 of 251,458 alleles) in gnomAD.
• PS4: This variant has been identified in more than 104 individuals with DGC, LBC or SRC tumours and whose families do not suggest HDGC. This variant was reported in a family with multiple gliomas and without gastric or lobular breast cancer (PMID: 33929593).
• BA1: This variant is present at a frequency of 0.00002 (6 of 251,458 alleles) in gnomAD.
• PP3: This variant is not predicted to impact splicing.