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_004360.3(CDH1):c.4G>A (p.Gly2Ser)

CA187442

183998 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a870dd72-f029-4e34-b558-341fb7b9051c

HGVS expressions

NM_004360.3:c.4G>A

NM_004360.3(CDH1):c.4G>A (p.Gly2Ser)

NC_000016.10:g.68737419G>A

CM000678.2:g.68737419G>A

NC_000016.9:g.68771322G>A

CM000678.1:g.68771322G>A

NC_000016.8:g.67328823G>A

NG_008021.1:g.5128G>A

ENST00000261769.10:c.4G>A

ENST00000261769.9:c.4G>A

ENST00000422392.6:c.4G>A

ENST00000566510.5:c.4G>A

ENST00000566612.5:c.4G>A

ENST00000611625.4:c.4G>A

ENST00000612417.4:c.4G>A

ENST00000621016.4:c.4G>A

NM_001317184.1:c.4G>A

NM_001317185.1:c.-1612G>A

NM_001317186.1:c.-1816G>A

NM_004360.4:c.4G>A

NM_004360.5:c.4G>A

NM_001317184.2:c.4G>A

NM_001317185.2:c.-1612G>A

NM_001317186.2:c.-1816G>A

NM_004360.5(CDH1):c.4G>A (p.Gly2Ser)

Likely Benign

BS2

PM3 PM1 PM4 PM5 PS2 PS3 PS1 PS4 PM6 PM2 BA1 PVS1 BP2 BP3 BP4 BP1 BP5 BP7 BS4 BS3 BS1 PP4 PP1 PP3 PP2

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 CDH1 c.4G>A (p.Gly2Ser) missense variant has a frequency of 0.00002 (2 of 128,626) in gnomAD, with a maximum allele frequency of 0.00008 (2 of 24,378) in the Latino subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; unpublished). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.

BS2

This variant has been observed in at least 20 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (SCV000213609.4, SCV000545414.5, SCV000566808.5). Therefore, this variant meets criteria for BS2, which specifies that the variant is seen in ≥10 individuals without DGC, SRC tumors, or LBC and whose families do not suggest HDGC.

PM3

PM3 does not apply to CDH1.

PM1

PM1 does not apply to CDH1.

PM4

PM4 does not apply to missense variants.

PM5

PM5 does not apply to CDH1.

PS2

This information is not available.

PS3

PS3 does not apply to missense variants.

PS1

To our knowledge, there are no known pathogenic variants in codon 2 of CDH1.

PS4

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

PM6

This information is not available.

PM2

This allele is observed at a frequency of 0.00002 (2 of 128,626) in gnomAD, with a maximum allele frequency of 0.00008 (2 of 24,378) in the Latino subpopulation. Therefore, this variant does not meet the minimum criteria for PM2, which requires a frequency of less than 1 in 100,000 alleles (0.00001) or less than 1 in 50,000 (0.00002) in a given subpopulation.

BA1

This allele is observed at a frequency of 0.00002 (2 of 128,626) in gnomAD, with a maximum allele frequency of 0.00008 (2 of 24,378) in the Latino subpopulation. Therefore, this variant does not meet the minimum criteria for BA1, which requires an allele frequency of greater than 0.002.

PVS1

PVS1 does not apply to missense variants.

BP2

This information is not available.

BP3

BP3 does not apply to CDH1.

BP4

BP4 does not apply to missense variants in CDH1.

BP1

BP1 does not apply to CDH1.

BP5

This variant was identified in an individual with other personal and family cancer history not suggestive of HDGC and with a pathogenic germline variant in BRCA2. Given a lack of cancer history consistent with HDGC and a confirmed variant in a gene associated with other inherited cancer syndromes, BP5 cannot be applied in this case.

BP7

BP7 does not apply to missense variants.

BS4

This information is not available.

BS3

BS3 does not apply to missense variants.

BS1

This allele is observed at a frequency of 0.00002 (2 of 128,626) in gnomAD, with a maximum allele frequency of 0.00008 (2 of 24,378) in the Latino subpopulation. Therefore, this variant does not meet the minimum criteria for BS1, which requires an allele frequency of greater than 0.001.

PP4

PP4 does not apply to CDH1.

PP1

This information is not available.

PP3

PP3 does not apply to missense variants in CDH1.

PP2

PP2 does not apply to CDH1.

Approved on: 2023-08-17

Published on: 2023-08-17

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