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]

Link to SEPIO compliant JSON-LD document

Variant: NM_004360.5(CDH1):c.69G>A (p.Gln23=)

CA193735

186050 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2823e92b-717a-4984-8f92-73b8b7effb19

HGVS expressions

NM_004360.5:c.69G>A

NM_004360.5(CDH1):c.69G>A (p.Gln23=)

NC_000016.10:g.68738317G>A

CM000678.2:g.68738317G>A

NC_000016.9:g.68772220G>A

CM000678.1:g.68772220G>A

NC_000016.8:g.67329721G>A

NG_008021.1:g.6026G>A

ENST00000261769.10:c.69G>A

ENST00000261769.9:c.69G>A

ENST00000422392.6:c.69G>A

ENST00000566510.5:c.69G>A

ENST00000566612.5:c.69G>A

ENST00000611625.4:c.69G>A

ENST00000612417.4:c.69G>A

ENST00000621016.4:c.69G>A

NM_004360.3:c.69G>A

NM_001317184.1:c.69G>A

NM_001317185.1:c.-1547G>A

NM_001317186.1:c.-1751G>A

NM_004360.4:c.69G>A

NM_001317184.2:c.69G>A

NM_001317185.2:c.-1547G>A

NM_001317186.2:c.-1751G>A

Likely Benign

BP7 PM2_Supporting BS2_Supporting

PVS1 BA1 BS4 BS3 BS1 BP5 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 PM6 PM3 PM1 PM4 PM5

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.69G>A (p.Glu23=) variant is absent from the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org). In silico splice site predictors do not suggest that this variant impacts splicing, and the G allele is not highly conserved across species (BP7).The variant has also been observed in >3 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2_Supporting; SCV000216307.4, SCV000545385.4, internal laboratory). Use of the Bayesian point system for this variant with conflicting evidence and classify this variant as likely benign. In summary, 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, BP7, BS2_Supporting.

BP7

In silico splice site predictors do not suggest that this variant impacts splicing, and the G allele is not highly conserved across species.

PM2_Supporting

This variant is absent from gnomAD.

BS2_Supporting

This variant has been observed in nine families not meeting IGCLC criteria for HDGC (SCV000216307.4, SCV000545385.4, internal laboratory).

PVS1

PVS1 does not apply to this variant.

BA1

This variant is absent from gnomAD.

BS4

To our knowledge, this variant has not been reported in individuals meeting IGCLC criteria for HDGC.

BS3

To our knowledge, this variant has not been evaluated for impact on splicing.

BS1

This variant is absent from gnomAD.

BP5

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

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

Splicing AI shows splicing effect however varSEAK shows no/low splicing effect.

BP1

BP1 does not apply to CDH1.

PS2

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

PS4

To our knowledge, this variant has not been reported in individuals meeting IGCLC criteria for HDGC.

PS3

To our knowledge, this variant has not been evaluated for impact on splicing.

PS1

PS1 does not apply to this variant.

PP4

PP4 does not apply to CDH1.

PP1

To our knowledge, this variant has not been reported in individuals meeting IGCLC criteria for HDGC.

PP3

Splicing AI shows splicing effect however varSEAK shows no/low splicing effect.

PP2

PP2 does not apply to CDH1.

PM6

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

PM3

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

PM1

PM1 does not apply to CDH1.

PM4

PM4 does not apply to this variant.

PM5

PM5 does not apply to CDH1.

Approved on: 2023-08-18

Published on: 2023-08-18

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