Variant: NM_004360.5(CDH1):c.49-3C>T

CA167975

142294 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 385373d2-025f-43b5-be8a-5c0aa6af9901

Approved on: 2023-08-17

Published on: 2023-08-17

HGVS expressions

NM_004360.5:c.49-3C>T
NM_004360.5(CDH1):c.49-3C>T
NC_000016.10:g.68738294C>T
CM000678.2:g.68738294C>T
NC_000016.9:g.68772197C>T
CM000678.1:g.68772197C>T
NC_000016.8:g.67329698C>T
NG_008021.1:g.6003C>T
ENST00000261769.10:c.49-3C>T
ENST00000261769.9:c.49-3C>T
ENST00000422392.6:c.49-3C>T
ENST00000566510.5:c.49-3C>T
ENST00000566612.5:c.49-3C>T
ENST00000611625.4:c.49-3C>T
ENST00000612417.4:c.49-3C>T
ENST00000621016.4:c.49-3C>T
NM_004360.3:c.49-3C>T
NM_001317184.1:c.49-3C>T
NM_001317185.1:c.-1567-3C>T
NM_001317186.1:c.-1771-3C>T
NM_004360.4:c.49-3C>T
NM_001317184.2:c.49-3C>T
NM_001317185.2:c.-1567-3C>T
NM_001317186.2:c.-1771-3C>T

Likely Benign

• Met criteria codes: BS2 BP4

• Not Met criteria codes: BS1 BS4 BS3 BP3 BP1 BP2 BP5 BP7 PS1 PS2 PS3 PS4 PM1 PM3 PM5 PM4 PM6 PM2 BA1 PP1 PP2 PP3 PP4 PVS1

Expert Panel

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.49-3C>T variant has been observed in at least 10 individuals without DGC, SRC tumours, or LBC & whose families do not suggest HDGC (BS2; SCV000186304.5, SCV000288486.4). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4.

Met criteria codes

• BS2: This variant was identified in 26 families who do not meet IGCLC criteria for HDGC (SCV000186304.5, SCV000288486.4).
• BP4: This variant is not predicted to alter splicing by multiple splice site predictors.

Not Met criteria codes

• BS1: This variant occurs at a frequency of 0.00002 (3 in 188,188) in gnomAD, with a maximum allele frequency of 0.00012 (2 in 17,020) in the African subpopulation.
• BS4: To our knowledge, segregation of this variant has not been reported in an HDGC family.
• BS3: To our knowledge, functional studies have not been reported for this variant.
• BP3: BP3 does not apply to CDH1.
• BP1: BP1 does not apply to CDH1.
• BP2: To our knowledge, this variant has not been reported in cis or trans with a pathogenic variant.
• BP5: To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.
• BP7: BP7 does not apply to intronic variants.
• PS1: PS1 does not apply to this variant.
• PS2: To our knowledge, this variant has not been reported as de novo.
• PS3: To our knowledge, functional studies have not been reported for this variant.
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: PM1 does not apply to CDH1.
• PM3: PM3 does not apply to CDH1.
• PM5: PM5 does not apply to CDH1.
• PM4: PM4 does not apply to this variant.
• PM6: To our knowledge, this variant has not been reported as de novo.
• PM2: This variant occurs at a frequency of 0.00002 (3 in 188,188) in gnomAD, with a maximum allele frequency of 0.00012 (2 in 17,020) in the African subpopulation. Therefore, this variant does not meet criteria for PM2.
• BA1: This variant occurs at a frequency of 0.00002 (3 in 188,188) in gnomAD, with a maximum allele frequency of 0.00012 (2 in 17,020) in the African subpopulation.
• PP1: To our knowledge, segregation of this variant has not been reported in an HDGC family.
• PP2: PP2 does not apply to CDH1.
• PP3: This variant is not predicted to alter splicing by multiple splice site predictors.
• PP4: PP4 does not apply to CDH1.
• PVS1: PVS1 does not apply to intronic variants.