Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_004360.5(CDH1):c.808T>G (p.Ser270Ala)

CA294235

142011 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f736f74f-a045-4573-aa21-41c5dfa9dd12

HGVS expressions

NM_004360.5:c.808T>G

NM_004360.5(CDH1):c.808T>G (p.Ser270Ala)

NC_000016.10:g.68810317T>G

CM000678.2:g.68810317T>G

NC_000016.9:g.68844220T>G

CM000678.1:g.68844220T>G

NC_000016.8:g.67401721T>G

NG_008021.1:g.78026T>G

ENST00000261769.10:c.808T>G

ENST00000261769.9:c.808T>G

ENST00000422392.6:c.808T>G

ENST00000561751.1:n.455-1367T>G

ENST00000562836.5:n.879T>G

ENST00000566510.5:c.652T>G

ENST00000566612.5:c.808T>G

ENST00000611625.4:c.808T>G

ENST00000612417.4:c.808T>G

ENST00000621016.4:c.808T>G

NM_004360.3:c.808T>G

NM_001317184.1:c.808T>G

NM_001317185.1:c.-808T>G

NM_001317186.1:c.-1012T>G

NM_004360.4:c.808T>G

NM_001317184.2:c.808T>G

NM_001317185.2:c.-808T>G

NM_001317186.2:c.-1012T>G

Benign

BS2 BA1

PVS1 BS4 BS3 BS1 BP7 BP5 BP3 BP2 BP4 BP1 PS2 PS3 PS4 PS1 PP1 PP4 PP3 PP2 PM6 PM2 PM5 PM4 PM3 PM1

Evidence Links 1

Expert Panel

CDH1 VCEP

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.808T>G (p.Ser270Ala) variant has a maximum subpopulation frequency of 0.002269 (0.2269%, 57 of 25124 alleles) in the European (Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1). This variant has also has been observed in more than 10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000185687.6, SCV000254832.8). In summary, this variant meets criteria to be classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BS2.

BS2

PMID: 11705864 - Detected in 5 of 923 controls. SCV000185687.6 (Ambry) - 23 families that do not meet HDGC clinical criteria. SCV000254832.8 (Invitae) - 43 families without CDH1 phenotypes described.

BA1

gnomAD 2.1.1 = 57 of 25124 alleles (0.2269%) in in Finnish populations (>0.2%). gnomAD 3.1 = 26 of 10598 alleles (0.2453%) in Finnish populations (>0.2%).

PVS1

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

Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli. PubMed:27582386

BS1

gnomAD 2.1.1 = 57 of 25124 alleles (0.2269%) in Finnish populations >0.2% and 9 of 7222 alleles (0.1246%) in others >0.1% and 59 of 129148 allelles (0.04568%) in Non-Finnish Europeans. gnomAD 3.1 = 26 of 10598 alleles (0.2453%) in Finnish populations and 25 of 68004 (0.03676%) in Non-Finnish Europeans.

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

BP3

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

BP4

VarSEAK - No splicing effect. SpliceAI - Donor Gain: score 0.03 at 12 bp.

BP1

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

PMID: 27582386 - Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli.

Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli. PubMed:27582386

PS4

PMID: 11705864 - 2 diffuse gastric cancer cases, but no ages provided. PMID: 26898890 - 1 breast/ovarian cancer, no pathology provided. PMID: 30333958 - 2 breast/ovarian cancer, no pathology provided. Ambry - none of the 23 families provided meets criteria (additional data for 70 probands could be made available).

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

PP3

VarSEAK - No splicing effect. SpliceAI - Donor Gain: score 0.03 at 12 bp.

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

PM2

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

Approved on: 2023-08-17

Published on: 2023-08-17

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