NM_004360.5(CDH1):c.2387G>A (p.Arg796Gln) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 6, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002271418.10

Allele description [Variation Report for NM_004360.5(CDH1):c.2387G>A (p.Arg796Gln)]

NM_004360.5(CDH1):c.2387G>A (p.Arg796Gln)

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.2387G>A (p.Arg796Gln)

HGVS:

NC_000016.10:g.68829745G>A
NG_008021.1:g.97454G>A
NM_001317184.2:c.2204G>A
NM_001317185.2:c.839G>A
NM_001317186.2:c.422G>A
NM_004360.5:c.2387G>AMANE SELECT
NP_001304113.1:p.Arg735Gln
NP_001304114.1:p.Arg280Gln
NP_001304115.1:p.Arg141Gln
NP_004351.1:p.Arg796Gln
LRG_301t1:c.2387G>A
LRG_301:g.97454G>A
NC_000016.9:g.68863648G>A
NM_004360.3:c.2387G>A
NM_004360.4:c.2387G>A
p.R796Q

Protein change:

R141Q

Links:

dbSNP: rs587782549

NCBI 1000 Genomes Browser:

rs587782549

Molecular consequence:

NM_001317184.2:c.2204G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.839G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001317186.2:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.2387G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000698383	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Oct 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004242735	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 6, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000698383

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Oct 2, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004242735

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 6, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698383.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: CDH1 c.2387G>A (p.Arg796Gln) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 403358 control chromosomes. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), suggesting that the variant is benign. A recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021). The following publication has been ascertained in the context of this evaluation (PMID: 33471991). Nine submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014; they reported the variant with conflicting assessments (Likely Benign n=3, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004242735.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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