NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 4, 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:: RCV001797632.9

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000698366	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Apr 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002067628	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 21, 2018)	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

SCV000698366

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Apr 4, 2023)

germline

clinical testing

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

Citation Link,

SCV002067628

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 21, 2018)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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, SCV000698366.3

#	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.1568A>G (p.Tyr523Cys) results in a non-conservative amino acid change located in the Cadherin-like domian (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 151000 control chromosomes (gnomAD v3.1.2), predominantly at a frequency of 0.0015 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 53 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, two as likely benign, and one as benign. 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 Genetic Services Laboratory, University of Chicago, SCV002067628.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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