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

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

Approved on: 2023-08-18

Published on: 2023-08-18

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

• Met criteria codes: PM2_Supporting BP7 BP4 BS2_Supporting

• Not Met criteria codes: BS3 BS4 BS1 BP5 BP3 BP2 BP1 PVS1 PM6 PS3 PS1 PS2 PS4 BA1 PM5 PM4 PM3 PM1 PP4 PP1 PP3 PP2

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

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.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD.
• BP7: This nucleotide is not highly conserved, with negative scores by PhyloP and GERP.
• 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.
• 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).

Not Met criteria codes

• 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.
• BP5: To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.
• 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.
• PVS1: PVS1 does not apply to this variant.
• PM6: To our knowledge, this variant has not been reported as de novo.
• 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.
• BA1: This variant is absent from gnomAD.
• 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.
• 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.