NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 23, 2023
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:: RCV000129330.18

Allele description [Variation Report for NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys)]

NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys)

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.1568A>G (p.Tyr523Cys)

Other names:

p.Y523C:TAT>TGT; NM_004360.5(CDH1):c.1568A>G

HGVS:

NC_000016.10:g.68819282A>G
NG_008021.1:g.86991A>G
NM_001317184.2:c.1385A>G
NM_001317185.2:c.20A>G
NM_001317186.2:c.-254-2719A>G
NM_004360.5:c.1568A>GMANE SELECT
NP_001304113.1:p.Tyr462Cys
NP_001304114.1:p.Tyr7Cys
NP_004351.1:p.Tyr523Cys
LRG_301t1:c.1568A>G
LRG_301:g.86991A>G
NC_000016.9:g.68853185A>G
NM_004360.3:c.1568A>G
NM_004360.4:c.1568A>G
p.Y523C

Protein change:

Y462C

Links:

dbSNP: rs553907248

NCBI 1000 Genomes Browser:

rs553907248

Molecular consequence:

NM_001317186.2:c.-254-2719A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001317184.2:c.1385A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.20A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.1568A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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LOC109566910 [Bos indicus]
LOC109566910 [Bos indicus]
Gene ID:109566910

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184093	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Sep 24, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29522266, 31780696 Citation Link,
SCV000689467	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29522266, 31780696, 25741868
SCV002529074	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Oct 10, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 31780696, 29522266, 32936981 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184093

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Sep 24, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000689467

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 23, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002529074

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Oct 10, 2021)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

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

Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico.

Dutil J, Teer JK, Golubeva V, Yoder S, Tong WL, Arroyo N, Karam R, Echenique M, Matta JL, Monteiro AN.

Sci Rep. 2019 Nov 28;9(1):17769. doi: 10.1038/s41598-019-54170-6.

PubMed [citation]

PMID:: 31780696
PMCID:: PMC6882826

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000184093.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000689467.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces tyrosine with cysteine at codon 523 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 29522266, 31780696). This variant has been identified in 9/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 Sema4, Sema4, SCV002529074.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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 13, 2024

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