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.49-8C>T

CA16608223

387465 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 555642f7-bae2-4755-84a5-d33f4e75cdc2

HGVS expressions

NM_004360.4:c.49-8C>T

NM_004360.4(CDH1):c.49-8C>T

NC_000016.10:g.68738289C>T

CM000678.2:g.68738289C>T

NC_000016.9:g.68772192C>T

CM000678.1:g.68772192C>T

NC_000016.8:g.67329693C>T

NG_008021.1:g.5998C>T

ENST00000261769.10:c.49-8C>T

ENST00000261769.9:c.49-8C>T

ENST00000422392.6:c.49-8C>T

ENST00000566510.5:c.49-8C>T

ENST00000566612.5:c.49-8C>T

ENST00000611625.4:c.49-8C>T

ENST00000612417.4:c.49-8C>T

ENST00000621016.4:c.49-8C>T

NM_004360.3:c.49-8C>T

NM_001317184.1:c.49-8C>T

NM_001317185.1:c.-1567-8C>T

NM_001317186.1:c.-1771-8C>T

NM_004360.5:c.49-8C>T

NM_001317184.2:c.49-8C>T

NM_001317185.2:c.-1567-8C>T

NM_001317186.2:c.-1771-8C>T

NM_004360.5(CDH1):c.49-8C>T

Likely Benign

BS2 BP4

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

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.49-8C>T is an intronic variant in the splice acceptor region of intron 1. This variant has an allele frequency of 0.00001 (2/150178) in gnomAD with a maximum frequency of 0.00003 (2/57282) in the European (Non-Finnish) sub-population. This variant has been reported in at least 12 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000529519.4, SCV000557406.3). This variant is predicted to have no impact on splicing by multiple in silico splice site predictors. HumanSpliceFinder predicts that this variant may create an exonic ESS site, but this effect has not been demonstrated experimentally to our knowledge (BP4). 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): BS2, BP4.

BS2

This variant has been observed in at least 12 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (SCV000529519.4, SCV000557406.3). This variant meets CDH1 VCEP criteria for BS2, which requires a minimum of 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC.

BP4

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

BS4

To our knowledge, segregation analysis of this variant in an HDGC family has not been reported.

BS3

To our knowledge, in vitro or in vivo splicing analysis has not been reported for this variant.

BS1

This variant has an allele frequency of 0.00001 (2/150178) in gnomAD with a maximum frequency of 0.00003 (2/57282) in the European (Non-Finnish) sub-population. Therefore, this variant does not meet the CDH1 VCEP criteria for BS1, which requires a minimum allele frequency of 0.1%.

BP5

This variant has been observed in one individual whose condition may be explained by a mosaic/de novo pathogenic variant (SCV000557406.3).

BP7

This rule does not apply to this variant.

BP2

To our knowledge, this variant has not been confirmed to occur in cis or trans with an established pathogenic variant nor as homozygous in an individual or family without DGC, SRC tumours or LBC.

BP3

This rule does not apply to CDH1.

BP1

This rule does not apply to CDH1.

PM6

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

PM2

This variant has an allele frequency of 0.00001 (2/150178) in gnomAD with a maximum frequency of 0.00003 (2/57282) in the European (Non-Finnish) sub-population. This variant does not meet the CDH1 VCEP criteria for PM2, which requires fewer than 1 in 50,000 alleles to be present in a given sub-population.

PS2

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

PS3

To our knowledge, in vitro or in vivo splicing analysis has not been reported for this variant.

PS4

This variant has been observed in one individual but whose condition may have been explained by a mosaic/de novo pathogenic variant (SCV000557406.3).

PS1

This rule does not apply to this variant.

BA1

This variant has an allele frequency of 0.00001 (2/150178) in gnomAD with a maximum frequency of 0.00003 (2/57282) in the European (Non-Finnish) sub-population. Therefore, this variant does not meet the CDH1 VCEP criteria for BA1, which requires a minimum allele frequency of 0.2%.

PM3

This rule does not apply to CDH1.

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.

PP1

To our knowledge, segregation analysis of this variant in an HDGC family has not been reported.

PP4

This rule does not apply to CDH1.

PP3

PP2

This rule does not apply to CDH1.

PVS1

This rule does not apply to this variant.

Approved on: 2023-08-17

Published on: 2023-08-17

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