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.49-9C>A

CA658798616

516511 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 22db38a0-5102-423e-b1e4-3c09530028b3

HGVS expressions

NM_004360.4:c.49-9C>A

NM_004360.4(CDH1):c.49-9C>A

NC_000016.10:g.68738288C>A

CM000678.2:g.68738288C>A

NC_000016.9:g.68772191C>A

CM000678.1:g.68772191C>A

NC_000016.8:g.67329692C>A

NG_008021.1:g.5997C>A

ENST00000261769.10:c.49-9C>A

ENST00000261769.9:c.49-9C>A

ENST00000422392.6:c.49-9C>A

ENST00000566510.5:c.49-9C>A

ENST00000566612.5:c.49-9C>A

ENST00000611625.4:c.49-9C>A

ENST00000612417.4:c.49-9C>A

ENST00000621016.4:c.49-9C>A

NM_004360.3:c.49-9C>A

NM_001317184.1:c.49-9C>A

NM_001317185.1:c.-1567-9C>A

NM_001317186.1:c.-1771-9C>A

NM_004360.5:c.49-9C>A

NM_001317184.2:c.49-9C>A

NM_001317185.2:c.-1567-9C>A

NM_001317186.2:c.-1771-9C>A

NM_004360.5(CDH1):c.49-9C>A

Likely Benign

BP4 BS2_Supporting PM2_Supporting

BS3 BS1 BS4 PVS1 BP7 BP5 BP3 BP1 BP2 PS3 PS1 PS4 PS2 BA1 PP3 PP2 PP1 PP4 PM6 PM1 PM4 PM5 PM3

Evidence Links 0

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.49-9C>A is an intronic variant in the splice acceptor region of intron 1. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; SCV000729557.1, SCV000760811.1). This variant is predicted to have no impact on splicing by multiple in silico splice site predictors. HumanSpliceFinder predicts that this variant may alter an exonic ESE site, but this effect has not been demonstrated experimentally to our knowledge (BP4). In summary, due to the use of the Bayesian point system for this variant with conflicting evidence, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2_Supporting, BP4.

BP4

This variant is predicted to have no impact on splicing by multiple in silico splice site predictors. HumanSpliceFinder predicts that this variant may alter an exonic ESE site, but this effect has not been demonstrated experimentally to our knowledge.

BS2_Supporting

This variant has been observed in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (SCV000729557.1, SCV000760811.1). At this time, these findings allow the use of BS2_Supporting for this variant.

PM2_Supporting

This variant has not been observed in gnomAD, ExAC, 1000 Genomes or ESP.

BS3

To our knowledge, this variant has not been reported in the literature.

BS1

This variant has not been observed in gnomAD.

BS4

To our knowledge, data supporting use of BS4 has not been observed.

PVS1

This rule does not apply to this variant.

BP7

This rule does not apply to this variant.

BP5

Observed in one individual with a likely pathogenic variant in CHEK2 (SCV000729557.1). Due to the moderate-penetrance nature of CHEK2, BP5 has not been applied to this variant.

BP3

This rule does not apply to CDH1.

BP1

This rule does not apply to CDH1.

BP2

To our knowledge, data supporting use of BP2 has not been observed.

PS3

To our knowledge, this variant has not been reported in the literature.

PS1

This rule does not apply to this variant.

PS4

To our knowledge, this variant has not been observed in a family meeting HDGC criteria.

PS2

To our knowledge, data supporting use of PS2 has not been observed.

BA1

This variant has not been observed in gnomAD.

PP3

PP2

This rule does not apply to CDH1.

PP1

To our knowledge, data supporting use of PP1 has not been observed.

PP4

This rule does not apply to CDH1.

PM6

To our knowledge, data supporting use of PM6 has not been observed.

PM1

This rule does not apply to CDH1.

PM4

This rule does not apply to this variant.

PM5

This rule does not apply to CDH1.

PM3

This rule does not apply to CDH1.

Approved on: 2023-08-18

Published on: 2023-08-18

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