NM_004360.5(CDH1):c.32TGC[7] (p.Leu14_Leu15dup) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 28, 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:: RCV000131585.13

Allele description [Variation Report for NM_004360.5(CDH1):c.32TGC[7] (p.Leu14_Leu15dup)]

NM_004360.5(CDH1):c.32TGC[7] (p.Leu14_Leu15dup)

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.32TGC[7] (p.Leu14_Leu15dup)

HGVS:

NC_000016.10:g.68737447TGC[7]
NG_008021.1:g.5156TGC[7]
NM_001317184.2:c.32TGC[7]
NM_001317185.2:c.-1584TGC[7]
NM_001317186.2:c.-1788TGC[7]
NM_004360.5:c.32TGC[7]MANE SELECT
NP_001304113.1:p.Leu14_Leu15dup
NP_004351.1:p.Leu14_Leu15dup
LRG_301t1:c.41_46dup
LRG_301:g.5156TGC[7]
NC_000016.10:g.68737447_68737449TGC[7]
NC_000016.9:g.68771347_68771348insGCTGCT
NC_000016.9:g.68771350TGC[7]
NM_004360.3:c.41_46dup
NM_004360.3:c.41_46dupTGCTGC
NM_004360.4:c.32_46TGC[7]
NM_004360.4:c.41_46dup
NM_004360.5(CDH1):c.32_34TGC[7]MANE SELECT
NM_004360.5:c.41_46dupMANE SELECT
p.L14_L15dup
p.Leu14_Leu15dup

Links:

dbSNP: rs587782476

NCBI 1000 Genomes Browser:

rs587782476

Molecular consequence:

NM_001317185.2:c.-1584TGC[7] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1788TGC[7] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.32TGC[7] - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_004360.5:c.32TGC[7] - inframe_insertion - [Sequence Ontology: SO:0001821]

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
SCV000186596	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jun 28, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000689536	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 9, 2023)	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

SCV000186596

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jun 28, 2023)

germline

clinical testing

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

Citation Link,

SCV000689536

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 9, 2023)

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

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, SCV000186596.9

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

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, SCV000689536.4

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

Description

This variant is a two amino acid duplication located in exon 1 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 1/124448 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

Last Updated: Sep 29, 2024

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