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]

Variant: NM_004360.5(CDH1):c.1320+1G>C

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA10588622

265635 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9edb42a6-d4f3-408e-857f-aa10c232bd15

Approved on: 2023-08-24

Published on: 2023-08-24

HGVS expressions

NM_004360.5:c.1320+1G>C

NM_004360.5(CDH1):c.1320+1G>C

NC_000016.10:g.68813496G>C

CM000678.2:g.68813496G>C

NC_000016.9:g.68847399G>C

CM000678.1:g.68847399G>C

NC_000016.8:g.67404900G>C

NG_008021.1:g.81205G>C

ENST00000261769.10:c.1320+1G>C

ENST00000261769.9:c.1320+1G>C

ENST00000422392.6:c.1137+1233G>C

ENST00000562836.5:n.1391+1G>C

ENST00000566510.5:c.1165G>C

ENST00000566612.5:c.1320+1G>C

ENST00000611625.4:c.1320+1G>C

ENST00000612417.4:c.1320+1G>C

ENST00000621016.4:c.1320+1G>C

NM_004360.3:c.1320+1G>C

NM_001317184.1:c.1137+1233G>C

NM_001317185.1:c.-295G>C

NM_001317186.1:c.-500+1G>C

NM_004360.4:c.1320+1G>C

NM_001317184.2:c.1137+1233G>C

NM_001317185.2:c.-295G>C

NM_001317186.2:c.-500+1G>C

Likely Pathogenic

PS4_Supporting PVS1_Strong PM5_Supporting PS3_Supporting PM2_Supporting

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

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.1320+1G>C variant occurs at the canonical splice donor site of exon 9 (PVS1_strong, PM5_supporting). This variant is absent from populations in gnomAD (PM2_supporting; http://gnomad.broadinstitute.org). Splicing analysis in vitro has shown that the C allele results in skipping of exon 9, producing an abnormal in-frame transcript (PS3_supporting; PMID: 8033105, 28301459). Furthermore, this variant has been observed in at least one family meeting IGCLC criteria for HDGC (PS4_supporting; SCV000322628.7). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_supporting, PS3_supporting, PS4_supporting, PM5_supporting.

PS4_Supporting

This variant was observed in an individual with gastric cancer in 20s with signet ring cells (GeneDx). This variant was reported in a family with blepharocheilodontic syndrome and gastric cancer (unknown histology) diagnosed under 35 years (PMID: 28301459).

PVS1_Strong

This variant occurs at the canonical splice donor site of exon 9.

PM5_Supporting

Apply PM5_Supporting to the variant with the alteration at canonical splicing site.

PS3_Supporting

This variant has been shown to result in skipping of exon 9, producing an abnormal in-frame transcript (PMID: 8033105, 28301459).

PM2_Supporting

This variant is absent from gnomAD.

BA1

This variant is absent from gnomAD.

BS2

BS4

This variant was shown to segregate with disease in a family with autosomal dominant blepharocheilodontic syndrome and gastric cancer diagnosed under 35 years in one carrier. However, pathology reports for this cancer were not available. To our knowledge, segregation of this variant has not been shown in a family meeting IGCLC criteria for HDGC.

BS3

This variant has been shown to result in skipping of exon 9, producing an abnormal in-frame transcript.

BS1

This variant is absent from gnomAD.

BP2

To our knowledge, this variant has not been reported in cis or trans with a pathogenic variant.

BP3

BP3 does not apply to CDH1.

BP4

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

BP1

BP1 does not apply to CDH1.

BP5

To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.

BP7

BP7 does not apply to this variant.

PS2

To our knowledge, this variant has not been reported as de novo.

PS1

To our knowledge, a previously established pathogenic variant at this position has not been reported.

PP1

PP4

PP4 does not apply to CDH1.

PP3

PP3 does not apply to this variant.

PP2

PP2 does not apply to CDH1.

PM6

To our knowledge, this variant has not been reported as de novo.

PM3

PM3 does not apply to CDH1.

PM4

PM4 does not apply to this variant.

PM1

PM1 does not apply to CDH1.

Curation History

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