Variant: NM_001317186.2:c.-684C>T

CA169895

142968 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 2595caa2-c7dd-44bd-ad69-2b5435bd9f8c

Approved on: 2023-08-03

Published on: 2023-08-03

HGVS expressions

NM_001317186.2:c.-684C>T
NC_000016.10:g.68812262C>T
CM000678.2:g.68812262C>T
NC_000016.9:g.68846165C>T
CM000678.1:g.68846165C>T
NC_000016.8:g.67403666C>T
NG_008021.1:g.79971C>T
ENST00000261769.10:c.1136C>T
ENST00000261769.9:c.1136C>T
ENST00000422392.6:c.1136C>T
ENST00000562836.5:n.1207C>T
ENST00000565810.1:n.180C>T
ENST00000566510.5:c.980C>T
ENST00000566612.5:c.1136C>T
ENST00000611625.4:c.1136C>T
ENST00000612417.4:c.1136C>T
ENST00000621016.4:c.1136C>T
NM_004360.3:c.1136C>T
NM_001317184.1:c.1136C>T
NM_001317185.1:c.-480C>T
NM_001317186.1:c.-684C>T
NM_004360.4:c.1136C>T
NM_004360.5:c.1136C>T
NM_001317184.2:c.1136C>T
NM_001317185.2:c.-480C>T
NM_004360.5(CDH1):c.1136C>T (p.Thr379Met)

Likely Benign

• Met criteria codes: BS2

• Not Met criteria codes: PP1 PP3 BA1 BS4 BS1 BP5 BP2 PS4

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.1136C>T (p.Thr379Met) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 2 of 152,226 alleles in the gnomAD 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 seen in more than 110 individuals without GC, DGC, gastric SRC tumours, and LBC and whose families do not suggest HDGC. This variant was also identified in a proband with family history of unspecified gastric cancer.

Not Met criteria codes

• PP1: To our knowledge, this variant has not been shown to segregate with disease in a family with HDGC.
• PP3: In silico predictors do not suggest that this variant alters splicing. Protein-based predictors for missense variants are not applicable for CDH1.
• BA1: This variant occurs at a frequency of 1.3x10-5% (2 in 152,226 alleles) in gnomAD v3.12.
• BS4: To our knowledge, this variant has not been shown to segregate with disease in a family with HDGC.
• BS1: This variant occurs at a frequency of 1.3x10-5% (2 in 152,226 alleles) in gnomAD v3.12.
• BP5: To our knowledge, this variant has not been identified in a family with HDGC and alternate molecular basis for disease.
• BP2: To our knowledge, this variant has not been reported in the homozygous state.
• PS4: This variant has been seen in more than 110 individuals without GC, DGC, gastric SRC tumours, and LBC and whose families do not suggest HDGC. This variant was also identified in a proband with family history of unspecified gastric cancer.