Evidence Repository - Clinical Genome Resources

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

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Variant: NM_004360.4(CDH1):c.1137G>A (p.Thr379=)

CA186229

156499 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3a1d0937-896d-4522-8899-90ddc6945ae1

HGVS expressions

NM_004360.4:c.1137G>A

NM_004360.4(CDH1):c.1137G>A (p.Thr379=)

NC_000016.10:g.68812263G>A

CM000678.2:g.68812263G>A

NC_000016.9:g.68846166G>A

CM000678.1:g.68846166G>A

NC_000016.8:g.67403667G>A

NG_008021.1:g.79972G>A

ENST00000261769.10:c.1137G>A

ENST00000261769.9:c.1137G>A

ENST00000422392.6:c.1137G>A

ENST00000562836.5:n.1208G>A

ENST00000565810.1:n.181G>A

ENST00000566510.5:c.981G>A

ENST00000566612.5:c.1137G>A

ENST00000611625.4:c.1137G>A

ENST00000612417.4:c.1137G>A

ENST00000621016.4:c.1137G>A

NM_004360.3:c.1137G>A

NM_001317184.1:c.1137G>A

NM_001317185.1:c.-479G>A

NM_001317186.1:c.-683G>A

NM_004360.5:c.1137G>A

NM_001317184.2:c.1137G>A

NM_001317185.2:c.-479G>A

NM_001317186.2:c.-683G>A

NM_004360.5(CDH1):c.1137G>A (p.Thr379=)

Pathogenic

PVS1_Moderate PS4 PS3 PM2_Supporting

BP2 BP3 BP1 BP4 BP5 BP7 PS2 PS1 BA1 PP1 PP4 PP2 PP3 PM6 PM3 PM4 PM1 PM5 BS2 BS4 BS3 BS1

Evidence Links 6

Expert Panel

CDH1 VCEP

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.1137G>A p.(Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 15831593). Additionally, this variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 15831593, 17545690, 17221870, 21681551, 27995193). 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 (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4.

PVS1_Moderate

Variant is in the last nucleotide of exon with in silico agreement of altered splicing.

PS4

Proband is an obligate carrier with a strong family history of DGC. Seven HDGC families with the c.1137G>A variant have been reported in the literature. Total of 8 families.

c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC. PubMed:27995193

c.1137G>A variant identified in proband with DGC at age 28 with a family history of DGC. Variant shown to generate an alternatively spliced transcript harbouring a PTC. PubMed:15831593

c.1137G>A variant identified in two families with histories of GC and DGC. PubMed:17545690

c.1137G>A variant identified in a proband with a family history of DGC and BC. PubMed:21681551

c.1137G>A variant identified in two families with personal or family histories of DGC. The authors additionally identify tumour evidence for loss of the wild type allele in one family member. PubMed:17221870

PS3

A c.1137G>A variant resulting in the generation of an alternatively spliced transcript harbouring a PTC has been reported in multiple HDGC families.

Allele-specific expression analysis demonstrated reduced expression of variant allele. PubMed:18427545

RT-PCR showed that the c.1137G>A variant results in complex aberrant splicing. PubMed:15831593

PM2_Supporting

Absent from population databases.

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

Multiple computational tools predict loss of donor splice site.

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

PS2

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

PS1

A c.1137G>A variant resulting in the generation of an alternatively spliced transcript harbouring a PTC has been reported in multiple HDGC families.

Allele-specific expression analysis demonstrated reduced expression of variant allele. PubMed:18427545

c.1137G>A variant identified in proband with DGC at age 28 with a family history of DGC. Variant shown to generate an alternatively spliced transcript harbouring a PTC. PubMed:15831593

BA1

Absent from population databases.

PP1

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

PP4

Proband is an obligate carrier with a strong family history of DGC. Several HDGC families with the c.1137G>A variant have been reported in the literature.

c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC. PubMed:27995193

c.1137G>A variant identified in proband with DGC at age 28 with a family history of DGC. Variant shown to generate an alternatively spliced transcript harbouring a PTC. PubMed:15831593

c.1137G>A variant identified in two families with histories of GC and DGC. PubMed:17545690

c.1137G>A variant identified in a proband with a family history of DGC and BC. PubMed:21681551

PP2

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

PP3

Multiple computational tools predict loss of donor splice site.

PM6

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

Variant is located at the same position as a previously established pathogenic splicing variant.

PM5

Allele-specific expression analysis demonstrated reduced expression of variant allele. PubMed:18427545

c.1137G>A variant identified in proband with DGC at age 28 with a family history of DGC. Variant shown to generate an alternatively spliced transcript harbouring a PTC. PubMed:15831593

BS2

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

A c.1137G>A variant resulting in the generation of an alternatively spliced transcript harbouring a PTC has been reported in multiple HDGC families.

BS1

Absent from population databases.

Approved on: 2023-08-29

Published on: 2023-08-29

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