Evidence Repository
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.113C>T (p.Thr38Met)

CA157971

133850 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 16b0578e-f7f0-408d-a64b-9eec636f4ec8
Approved on: 2023-08-18
Published on: 2023-08-18

HGVS expressions

NM_004360.5:c.113C>T
NM_004360.5(CDH1):c.113C>T (p.Thr38Met)
NC_000016.10:g.68738361C>T
CM000678.2:g.68738361C>T
NC_000016.9:g.68772264C>T
CM000678.1:g.68772264C>T
NC_000016.8:g.67329765C>T
NG_008021.1:g.6070C>T
ENST00000261769.10:c.113C>T
ENST00000261769.9:c.113C>T
ENST00000422392.6:c.113C>T
ENST00000566510.5:c.113C>T
ENST00000566612.5:c.113C>T
ENST00000611625.4:c.113C>T
ENST00000612417.4:c.113C>T
ENST00000621016.4:c.113C>T
NM_004360.3:c.113C>T
NM_001317184.1:c.113C>T
NM_001317185.1:c.-1503C>T
NM_001317186.1:c.-1707C>T
NM_004360.4:c.113C>T
NM_001317184.2:c.113C>T
NM_001317185.2:c.-1503C>T
NM_001317186.2:c.-1707C>T

Likely Benign

Met criteria codes 2
BS2 PM2_Supporting
Not Met criteria codes 24
PVS1 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS4 PS2 PS3 PS1 BA1 PP4 PP1 PP3 PP2 PM6 PM3 PM1 PM4 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.113C>T (p.Thr38Met) variant results in a non-synonymous amino acid substitution in exon 2 of CDH1. The variant allele occurs in 1 of 156,704 alleles in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in 1 of 1,362 alleles among individuals undergoing genome sequencing who are not known to meet IGCLC criteria for HDGC (PMID: 24728327). In addition, this variant has been observed in at least 10 individuals without DGC, LBC or SRC tumors and whose families do not suggest HDGC (BS2; SCV000666274.3, SCV000567622.4, SCV000954584.2). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, PM2_supporting.
Met criteria codes
BS2
This variant has been reported in 11 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (SCV000666274.3, SCV000567622.4, SCV000954584.2). In addition, this variant was identified in four individuals with unclear phenotypes: two individuals for whom family history was not reported, one individual with one reported gastric cancer in their family, and one individual with bilateral breast cancer (DCIS and unknown pathology) with a family history of gastric cancer (unknown pathology) in three second-degree relatives (GeneDx).
PM2_Supporting
This allele occurs at a frequency of 0.00001 (1 in 156,704 alleles) in gnomAD v2. Note that this allele occurs at a frequency of 0.00001395 (2 in 143,328 alleles) in gnomAD v3, with a maximum frequency of 0.0001464 (2 in 13,662 alleles) in the Latino subpopulation.
Not Met criteria codes
PVS1
PVS1 does not apply to this variant.
BS4
Segregation data not available.
BS3
No functional assays demonstrating an impact on splicing have been reported.
BS1
This allele occurs at a frequency of 0.00001 (1 in 156,704 alleles) in gnomAD v2. Note that this allele occurs at a frequency of 0.00001395 (2 in 143,328 alleles) in gnomAD v3, with a maximum frequency of 0.0001464 (2 in 13,662 alleles) in the Latino subpopulation.
BP2
To our knowledge, this variant has not been reported in cis or trans with a pathogenic variant.
BP3
BP3 does not apply to CDH1.
BP4
This variant is not predicted to impact splicing by multiple computational tools.
BP1
BP1 does not apply to CDH1.
BP5
This variant has not been identified in a family meeting IGCLC criteria for HDGC with an alternate molecular basis for disease.
BP7
BP7 does not apply to this variant.
PS4
This variant has been reported in 11 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (Ambry, GeneDx, Invitae). In addition, this variant was identified in four individuals with unclear phenotypes: two individuals for whom family history was not reported, one individual with one reported gastric cancer in their family, and one individual with bilateral breast cancer (DCIS and unknown pathology) with a family history of gastric cancer (unknown pathology) in three second-degree relatives (GeneDx).
PS2
To our knowledge, this variant has not been reported as de novo.
PS3
No functional assays demonstrating an impact on splicing have been reported.
PS1
A pathogenic variant at this position has not been established.
BA1
This allele occurs at a frequency of 0.00001 (1 in 156,704 alleles) in gnomAD v2. Note that this allele occurs at a frequency of 0.00001395 (2 in 143,328 alleles) in gnomAD v3, with a maximum frequency of 0.0001464 (2 in 13,662 alleles) in the Latino subpopulation.
PP4
PP4 does not apply to CDH1.
PP1
Segregation data not available.
PP3
This variant is not predicted to impact splicing by multiple computational tools.
PP2
PP2 does not apply to CDH1.
PM6
To our knowledge, this variant has not been reported as de novo.
PM3
PM3 does not apply to CDH1.
PM1
PM1 does not apply to CDH1.
PM4
PM4 does not apply to this variant.
PM5
PM5 does not apply to CDH1.
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