Variant: NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp)

CA8130235

418841 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: c46e3e12-7172-498b-86a7-d9cd9f01bbee

HGVS expressions

NM_004360.5:c.2245C>T
NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp)
NC_000016.10:g.68828254C>T
CM000678.2:g.68828254C>T
NC_000016.9:g.68862157C>T
CM000678.1:g.68862157C>T
NC_000016.8:g.67419658C>T
NG_008021.1:g.95963C>T
ENST00000261769.10:c.2245C>T
ENST00000261769.9:c.2245C>T
ENST00000422392.6:c.2062C>T
ENST00000562118.1:n.463C>T
ENST00000562836.5:n.2316C>T
ENST00000566510.5:c.*911C>T
ENST00000566612.5:c.*485C>T
ENST00000611625.4:c.2308C>T
ENST00000612417.4:c.1853+1700C>T
ENST00000621016.4:c.1866-5949C>T
NM_004360.3:c.2245C>T
NM_001317184.1:c.2062C>T
NM_001317185.1:c.697C>T
NM_001317186.1:c.280C>T
NM_004360.4:c.2245C>T
NM_001317184.2:c.2062C>T
NM_001317185.2:c.697C>T
NM_001317186.2:c.280C>T

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: PS2 PS4 PS3 PS1 PP1 PP4 PP2 PP3 PM3 PM1 PM4 PM5 PM6 BA1 BS2 PVS1 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP1 BP4

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 NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) variant is a missense variant in exon 14 and results in the change of an Arginine to a Tryptophan. This variant is present in <1/100,000 alleles in the ExAC and gnomAD cohort (PM2_Supporting). Furthermore, it has been observed in > 10 individuals (34) without DGC, SRC tumours or LBC and whose families do not suggest HDGC. This variant has been reported in four families meeting HDGC clinical criteria, however, this represents only 11% of all families carrying this variant (threshold is 30% to consider applying PS4). Given that multiple families with this variants meet the HDGC criteria, CDH1-VCEP recommended not to apply BS2 code. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting.

Met criteria codes

• PM2_Supporting: NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) occurs at an allele frequency of 0.000003976 (1/251478) in gnomAD v2.1.1.

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: 4 families meet HDGC criteria, however, this is bellow 30% of all families carrying the NM_004360.5:c.2245C>T variant. Furthermore, two carriers have LBC and one carrier has SRCC diagnosed between 50 and 60 years old.
• PS3: Several original articles published by one research laboratory demonstrate the functional impact of this variant in E-cadherin expression and localization in a cancer cell line, nevertheless, further research on this subject is required.
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: Single case reported at Ambry, family did not meet HDGC criteria (Proband unknown, 2 cases breast cancer unspecified, 1 case gastric cancer unspecified)
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: Exceeds impact threshold in REVEL. Splicing only for CDH1.
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: This variant has been observed in 34 heterozygous 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 five individuals with family history of unspecified gastric cancer.
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: Exceeds impact threshold in REVEL. Splicing only for CDH1.

Approved on: 2023-08-28

Published on: 2023-09-27