NM_004360.5(CDH1):c.1571G>A (p.Arg524Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000216734.8

Allele description [Variation Report for NM_004360.5(CDH1):c.1571G>A (p.Arg524Gln)]

NM_004360.5(CDH1):c.1571G>A (p.Arg524Gln)

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.1571G>A (p.Arg524Gln)

HGVS:

NC_000016.10:g.68819285G>A
NG_008021.1:g.86994G>A
NM_001317184.2:c.1388G>A
NM_001317185.2:c.23G>A
NM_001317186.2:c.-254-2716G>A
NM_004360.5:c.1571G>AMANE SELECT
NP_001304113.1:p.Arg463Gln
NP_001304114.1:p.Arg8Gln
NP_004351.1:p.Arg524Gln
LRG_301t1:c.1571G>A
LRG_301:g.86994G>A
NC_000016.9:g.68853188G>A
NM_004360.3:c.1571G>A
NM_004360.4:c.1571G>A

Protein change:

R463Q

Links:

dbSNP: rs761180883

NCBI 1000 Genomes Browser:

rs761180883

Molecular consequence:

NM_001317186.2:c.-254-2716G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001317184.2:c.1388G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.23G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.1571G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000274712	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000908741	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 17, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004611137	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 19, 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

SCV000274712

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 13, 2023)

germline

clinical testing

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

Citation Link,

SCV000908741

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 17, 2018)

germline

clinical testing

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

SCV004611137

KCCC/NGS Laboratory, Kuwait Cancer Control Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 19, 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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

Garcia-Pelaez J, Barbosa-Matos R, Lobo S, Dias A, Garrido L, Castedo S, Sousa S, Pinheiro H, Sousa L, Monteiro R, Maqueda JJ, Fernandes S, Carneiro F, Pinto N, Lemos C, Pinto C, Teixeira MR, Aretz S, Bajalica-Lagercrantz S, Balmaña J, Blatnik A, Benusiglio PR, et al.

Lancet Oncol. 2023 Jan;24(1):91-106. doi: 10.1016/S1470-2045(22)00643-X. Epub 2022 Nov 24. Erratum in: Lancet Oncol. 2023 Jan;24(1):e10. doi: 10.1016/S1470-2045(22)00761-6.

PubMed [citation]

PMID:: 36436516
PMCID:: PMC9810541

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 Ambry Genetics, SCV000274712.7

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

Description

The p.R524Q variant (also known as c.1571G>A), located in coding exon 11 of the CDH1 gene, results from a G to A substitution at nucleotide position 1571. The arginine at codon 524 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was identified in an individual with a history of breast cancer (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV000908741.2

#	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

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004611137.1

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the CDH1 protein (p.Arg524Gln). This variant is present in population databases (rs761180883, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 230993). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic/likely pathogenic variants in the CDH1 gene cause Diffuse gastric and lobular breast cancer syndrome (OMIM 137215).

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

Last Updated: Sep 29, 2024

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