Variant: NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys)

CA090925

141014 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 19eabdee-a252-43c4-a1f4-f09d37e205e2

Approved on: 2023-08-03

Published on: 2023-08-03

HGVS expressions

NM_004360.5:c.1568A>G
NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys)
NC_000016.10:g.68819282A>G
CM000678.2:g.68819282A>G
NC_000016.9:g.68853185A>G
CM000678.1:g.68853185A>G
NC_000016.8:g.67410686A>G
NG_008021.1:g.86991A>G
ENST00000261769.10:c.1568A>G
ENST00000261769.9:c.1568A>G
ENST00000422392.6:c.1385A>G
ENST00000562836.5:n.1639A>G
ENST00000566510.5:c.*234A>G
ENST00000566612.5:c.1566-2719A>G
ENST00000611625.4:c.1631A>G
ENST00000612417.4:c.1568A>G
ENST00000621016.4:c.1568A>G
NM_004360.3:c.1568A>G
NM_001317184.1:c.1385A>G
NM_001317185.1:c.20A>G
NM_001317186.1:c.-254-2719A>G
NM_004360.4:c.1568A>G
NM_001317184.2:c.1385A>G
NM_001317185.2:c.20A>G
NM_001317186.2:c.-254-2719A>G

Benign

• Met criteria codes: BP2_Strong BS2 BS1

• Not Met criteria codes: BA1 PM2

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 filtering allele frequency of the c.1568A>G (p.Tyr523Cys) variant in the CDH1 gene is 0.15% for Latino/Admixed American chromosomes in gnomAD (95% CI of 23/15282), which meets the allele frequency threshold defined by the ClinGen CDH1 Variant Curation Expert Panel for considering strong evidence against pathogenicity for autosomal dominant hereditary diffuse gastric cancer variants (BS1). This variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 9 individuals without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023)

Met criteria codes

• BP2_Strong: This variant is observed in the homozygous state in 9 individuals without personal and/or family history of DGC, LBC, or SRC tumors (BP2; GeneDx and Invitae).
• BS2: This variant has been observed in 114 heterozygous and 9 homozygous individuals with no diffuse gastric cancer, signet ring cell carcinoma or lobular breast cancer and/or whose family histories do not suggest HDGC (BS2; GeneDX, Ambry, Invitae). Note that this includes seven individual with family history of unspecified gastric cancer. Three additional probands are known to have LBC.
• BS1: The highest population minor allele frequency in gnomAD v3.1.2 is 0.001505 (23/15282 alleles) in the Latino/Admixed American population, which is higher than the ClinGen CDH1 VCEP threshold (>0.001) for BS1, and therefore meets this criterion (BS1)

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline