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_004360.5(CDH1):c.120G>A (p.Thr40=)

CA188783

184377 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5ff7f54c-35a4-4b6b-a1d0-1a7350acb673

HGVS expressions

NM_004360.5:c.120G>A

NM_004360.5(CDH1):c.120G>A (p.Thr40=)

NC_000016.10:g.68738368G>A

CM000678.2:g.68738368G>A

NC_000016.9:g.68772271G>A

CM000678.1:g.68772271G>A

NC_000016.8:g.67329772G>A

NG_008021.1:g.6077G>A

ENST00000261769.10:c.120G>A

ENST00000261769.9:c.120G>A

ENST00000422392.6:c.120G>A

ENST00000566510.5:c.120G>A

ENST00000566612.5:c.120G>A

ENST00000611625.4:c.120G>A

ENST00000612417.4:c.120G>A

ENST00000621016.4:c.120G>A

NM_004360.3:c.120G>A

NM_001317184.1:c.120G>A

NM_001317185.1:c.-1496G>A

NM_001317186.1:c.-1700G>A

NM_004360.4:c.120G>A

NM_001317184.2:c.120G>A

NM_001317185.2:c.-1496G>A

NM_001317186.2:c.-1700G>A

Likely Benign

PM2_Supporting BP4 BP7 BS2_Supporting

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

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.120G>A (p.Thr40=) variant results in a synonymous amino acid change in exon 2. Although this variant is absent from gnomAD (PM2_Supporting), it has been observed internally in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting, SCV000214188.4, SCV001041247.2). In addition, this variant is not predicted to result in aberrant splicing and is not highly conserved (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting, BP4, BP7, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD.

BP4

Aberrant splicing is not supported by multiple computational tools. HSF predicts activation of an exonic cryptic acceptor site, but this has not been validated to our knowledge.

BP7

This nucleotide is not highly conserved, with negative scores by PhyloP and GERP.

BS2_Supporting

This variant has been observed in 6 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (SCV000214188.4, SCV001041247.2).

BA1

This variant is absent from gnomAD.

PVS1

PVS1 does not apply to this variant.

BS3

To our knowledge, the function of this variant has not been assessed in vitro or in vivo.

BS4

To our knowledge, segregation of this variant has not been reported in families with HDGC.

BS1

This variant is absent from gnomAD.

BP3

BP3 does not apply to CDH1.

BP2

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

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.

PS3

To our knowledge, the function of this variant has not been assessed in vitro or in vivo.

PS1

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

PS2

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

PS4

This variant has been observed in 6 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC.

PP4

PP4 does not apply to CDH1.

PP1

To our knowledge, segregation of this variant has not been reported in families with HDGC.

PP3

Aberrant splicing is not supported by multiple computational tools. HSF predicts activation of an exonic cryptic acceptor site, but this has not been validated to our knowledge.

PP2

PP2 does not apply to CDH1.

PM5

PM5 does not apply to CDH1.

PM4

PM4 does not apply to this variant.

PM3

PM3 does not apply to CDH1.

PM1

PM1 does not apply to CDH1.

PM6

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

Approved on: 2023-08-18

Published on: 2023-08-18

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