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]
Link to SEPIO compliant JSON-LD document

Variant: NM_004360.5(CDH1):c.715G>A (p.Gly239Arg)

CA298980

132709 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ed68928a-1184-400b-9e8e-8f8e92950551

HGVS expressions

NM_004360.5:c.715G>A
NM_004360.5(CDH1):c.715G>A (p.Gly239Arg)
NC_000016.10:g.68810224G>A
CM000678.2:g.68810224G>A
NC_000016.9:g.68844127G>A
CM000678.1:g.68844127G>A
NC_000016.8:g.67401628G>A
NG_008021.1:g.77933G>A
ENST00000261769.10:c.715G>A
ENST00000261769.9:c.715G>A
ENST00000422392.6:c.715G>A
ENST00000561751.1:n.454+1376G>A
ENST00000562836.5:n.786G>A
ENST00000566510.5:c.559G>A
ENST00000566612.5:c.715G>A
ENST00000611625.4:c.715G>A
ENST00000612417.4:c.715G>A
ENST00000621016.4:c.715G>A
NM_004360.3:c.715G>A
NM_001317184.1:c.715G>A
NM_001317185.1:c.-901G>A
NM_001317186.1:c.-1105G>A
NM_004360.4:c.715G>A
NM_001317184.2:c.715G>A
NM_001317185.2:c.-901G>A
NM_001317186.2:c.-1105G>A

Pathogenic

Met criteria codes 4
PM2_Supporting PS3 PS4 PP3
Not Met criteria codes 22
PS2 PS1 PP1 PP4 PP2 PM5 PM3 PM4 PM1 PM6 BA1 BS2 PVS1 BS4 BS1 BS3 BP7 BP5 BP2 BP3 BP4 BP1

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.715G>A (p.Gly239Arg) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 16 families (18) meeting HDGC clinical criteria (PS4_very strong; PMID: 17545690, 23264079, 23264079, 26182300; SCV000153869.9, SCV000273881.6, internal laboratory contributors). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). There are RNA assays demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690, 33619332). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (v3.1): PS4_very strong, PS3, PM2_supporting, PP3.
Met criteria codes
PM2_Supporting
Absent in gnomAD 2.1.1 and 3.1.
PS3
PMID: 17545690 - RNA studies (patient RNA and minigene assays) have detected an abnormal out of frame transcript with the first 29 base pairs of exon 6 deleted in individuals with this alteration. PMID: 33619332 - Deletion of 29 nucleotides from the 5′ end of exon 6 was seen in 54% of analysed clones. CDH1 r.906g>a (c.715A) transcript may result in full-length product with the mutant “A” transcript at CDH1 c.715 position in about 1% of the transcripts. PMID: 17221870 - Protein studies show that this variant confers deficient E-cadherin function with respect to intercellular adhesion and suppression of invasion in vitro. PMID: 19268661 - increased motility with reduced affinity for EGFR and higher EGFR activation.
PS4
18 probands/families meet HDGC phenotype criteria and very strong evidence level of PS4 is applied. PMID: 17545690 - 4 cases of gastric cancer (1 diffuse) in one family - meets HDGC criteria. PMID: 17221870 - one proband with DGC at 30 years, mother died of DGC 29 years old - meets HDGC criteria. PMID: 23264079 - 28-year-old male with diffuse gastric cancer - meets HDGC criteria. PMID: 26182300 - DGC at 31 years old - meets HDGC criteria. PMID: 16924464 - reported as HDGC, but no clinical details. PMID: 26845104 - gastric cancer, but no pathology. PMID: 28873162 - advanced cancer, but no pathology. PMID: 26681312 - breast cancer, but no pathology. SCV000153869.9 (Invitae) - 5 families meet criteria. SCV000273881.6 (Ambry) - one family meets criteria. GeneDx - none meets criteria. NCI - 8 families meet criteria.
PP3
SpliceAI: Acceptor Gain - score = 0.97 at 2 bp downstream of the variant. Acceptor Loss - score = 0.11 at -27 bp. Donor Loss - score = 0.07 at 38 bp. SSF, MaxENT and NNSplice - predict that the variant creates a 3' acceptor site (at c.717) without a significant impact on the canonical splice site.
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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
PM5
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
PM4
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
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
SCV000210903.14 (Genedx) - 3 families (there is breast cancer in every family, no gastric). SCV000153869.9 (Invitae) - 3 families (breast cancer, no gastric). Ambry - 2 families (no gastric) BS2 cannot be applied to variants in which more than 30% of reported individuals meet HDGC criteria.
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
BS1
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
BP7
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
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
BP4
VarSEAK: Class 1, No splicing effect.
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-08-29
Published on: 2023-08-29
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