Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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
Link to MONDO
UUID: c46e3e12-7172-498b-86a7-d9cd9f01bbee
Approved on: 2023-08-28
Published on: 2023-09-27

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
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Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 25
PS4 PS1 PS2 PS3 PP1 PP2 PP3 PP4 PVS1 PM6 PM1 PM3 PM5 PM4 BA1 BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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.
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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.
PP4
Single case reported at Ambry, family did not meet HDGC criteria (Proband unknown, 2 cases breast cancer unspecified, 1 case gastric cancer unspecified)
PVS1
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
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
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
PM4
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.
BS1
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
BP4
Exceeds impact threshold in REVEL. Splicing only for CDH1.
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
BP2
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
Curation History
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