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.297G>A (p.Leu99=)

CA10580080

233145 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 66fa3d0a-0c88-4829-b305-3ca735915a4a

HGVS expressions

NM_004360.5:c.297G>A
NM_004360.5(CDH1):c.297G>A (p.Leu99=)
NC_000016.10:g.68801803G>A
CM000678.2:g.68801803G>A
NC_000016.9:g.68835706G>A
CM000678.1:g.68835706G>A
NC_000016.8:g.67393207G>A
NG_008021.1:g.69512G>A
ENST00000261769.10:c.297G>A
ENST00000261769.9:c.297G>A
ENST00000422392.6:c.297G>A
ENST00000561751.1:n.64G>A
ENST00000562836.5:n.368G>A
ENST00000564676.5:n.579G>A
ENST00000564745.1:n.292G>A
ENST00000566510.5:c.297G>A
ENST00000566612.5:c.297G>A
ENST00000611625.4:c.297G>A
ENST00000612417.4:c.297G>A
ENST00000621016.4:c.297G>A
NM_004360.3:c.297G>A
NM_001317184.1:c.297G>A
NM_001317185.1:c.-1319G>A
NM_001317186.1:c.-1523G>A
NM_004360.4:c.297G>A
NM_001317184.2:c.297G>A
NM_001317185.2:c.-1319G>A
NM_001317186.2:c.-1523G>A

Likely Benign

Met criteria codes 4
PM2_Supporting BS2_Supporting BP7 BP4
Not Met criteria codes 22
PVS1 BA1 BP5 BP2 BP3 BP1 BS4 BS3 BS1 PP4 PP1 PP3 PP2 PM6 PS4 PS1 PS2 PS3 PM5 PM3 PM1 PM4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.297G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Leu99=) that is not predicted by SpliceAI, SSF, MaxEnt to impact splicing (BP4, BP7). In addition, it occurs at a nucleotide that is not conserved as shown by phastCons and (BP7). This variant has been observed in more than 3 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2_Supporting, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022)
Met criteria codes
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
BS2_Supporting
This variant has been observed in more than 3 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2_supporting; Invitae, Ambry).
BP7
The results from 3 in silico predictors, [SpliceAI maxDelta = 0.01 (acceptor loss), SSF (null --> 70.35) and MaxEnt (null -->2.84)], suggest that the variant does not impact CDH1 function via altering splicing In addition, it occurs at a nucleotide that is not conserved as shown by [phastCons = 0, phyloP=-1.25] (BP7).
BP4
The results from 3 in silico predictors, [SpliceAI maxDelta = 0.01 (acceptor loss), SSF (null --> 70.35) and MaxEnt (null -->2.84)], suggest that the variant does not impact CDH1 function via altering splicing (BP4)
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-08-02
Published on: 2023-08-02
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