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]

Variant: NM_004360.5(CDH1):c.1057G>A (p.Glu353Lys)

CA10577540

234571 (ClinVar)

Gene: CDH1 (HGNC:999)
Condition: CDH1-related diffuse gastric and lobular breast cancer (MONDO:0007648)
Inheritance Mode: Autosomal dominant inheritance
UUID: 60a7410c-1a25-4d28-8b31-90b524be8a48
Approved on: 2023-08-24
Published on: 2023-08-24

HGVS expressions

NM_004360.5(CDH1):c.1057G>A (p.Glu353Lys)
NM_004360.5:c.1057G>A
NC_000016.10:g.68812183G>A
CM000678.2:g.68812183G>A
NC_000016.9:g.68846086G>A
CM000678.1:g.68846086G>A
NC_000016.8:g.67403587G>A
NG_008021.1:g.79892G>A
ENST00000261769.10:c.1057G>A
ENST00000261769.9:c.1057G>A
ENST00000422392.6:c.1057G>A
ENST00000561751.1:n.679G>A
ENST00000562836.5:n.1128G>A
ENST00000565810.1:n.101G>A
ENST00000566510.5:c.901G>A
ENST00000566612.5:c.1057G>A
ENST00000611625.4:c.1057G>A
ENST00000612417.4:c.1057G>A
ENST00000621016.4:c.1057G>A
NM_004360.3:c.1057G>A
NM_001317184.1:c.1057G>A
NM_001317185.1:c.-559G>A
NM_001317186.1:c.-763G>A
NM_004360.4:c.1057G>A
NM_001317184.2:c.1057G>A
NM_001317185.2:c.-559G>A
NM_001317186.2:c.-763G>A
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS4_Moderate PS3 PP3
Not Met criteria codes 21
PVS1 BS2 BS4 BS1 BS3 BP3 BP4 BP1 BP7 BP5 PS2 PS1 PP1 PP4 PP2 BA1 PM5 PM4 PM3 PM1 PM6

Evidence Links 1

Expert Panel

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.1057G>A (p.Glu353Lys) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_moderate; SCV001378233.1, SCV000580696.4). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 32133419). This variant is predicted to affect splicing by SpliceAI (Donor Gain: score = 0.54 at -3 bp) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (v3.1): PS3, PS4_moderate, PM2_supporting, PP3.
Met criteria codes
PM2_Supporting
Absent in gnomAD 2.1.1 and 3.1.
PS4_Moderate
SCV001378233.1 (Invitae) - 1 family meets criteria (proband GIST but father signet cell gastric adenocarcinoma in 30s) SCV000580696.4 (Ambry) - 1 family meets criteria (3 cases stomach, including 1 diffuse in 20s)
PS3
PMID: 32133419 - RNA studies demonstrate abnormal splicing in the set of samples tested (Ambry internal data) - CDH1 r.1055_1137del (out-of-frame).
RNA studies demonstrate abnormal splicing, r.1055_1137del (out-of-frame). PubMed:32133419
PP3
SpliceAI - Donor Gain: score = 0.54 at -3 bp (upstream of the variant), c.1055. SSF = 90.31->94.67 (+4.8%). MaxENT = 9.16->10.51 (+14.8%). NNSPLICE = 0.99->1.00 (+0.8%).
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
GeneDx - 1 family (some with breast cancer). Invitae - 1 family (breast, no gastric). Ambry - 1 family (breast, no gastric). BS2 cannot be applied to variants in which more than 30% of reported individuals meet HDGC criteria.
BS4
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
BS3
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
BP4
VarSEAK: 5' DONOR SPLICE SITE PREDICTION - Likely no splicing effect.
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
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
PS2
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
PP1
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
PP2
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
PM5
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
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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