NM_004360.5(CDH1):c.125C>T (p.Pro42Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 14, 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:: RCV000214968.12

Allele description [Variation Report for NM_004360.5(CDH1):c.125C>T (p.Pro42Leu)]

NM_004360.5(CDH1):c.125C>T (p.Pro42Leu)

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.125C>T (p.Pro42Leu)

Other names:

NM_004360.5(CDH1):c.125C>T

HGVS:

NC_000016.10:g.68738373C>T
NG_008021.1:g.6082C>T
NM_001317184.2:c.125C>T
NM_001317185.2:c.-1491C>T
NM_001317186.2:c.-1695C>T
NM_004360.5:c.125C>TMANE SELECT
NP_001304113.1:p.Pro42Leu
NP_004351.1:p.Pro42Leu
LRG_301t1:c.125C>T
LRG_301:g.6082C>T
NC_000016.9:g.68772276C>T
NM_004360.3:c.125C>T
NM_004360.4:c.125C>T
p.Pro42Leu

Protein change:

P42L

Links:

dbSNP: rs876659333

NCBI 1000 Genomes Browser:

rs876659333

Molecular consequence:

NM_001317185.2:c.-1491C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1695C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.125C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.125C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000275688	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Feb 14, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000689440	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30256826, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000275688

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Feb 14, 2024)

germline

clinical testing

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

Citation Link,

SCV000689440

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 17, 2023)

germline

clinical testing

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

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

Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.

Martin-Morales L, Rofes P, Diaz-Rubio E, Llovet P, Lorca V, Bando I, Perez-Segura P, de la Hoya M, Garre P, Garcia-Barberan V, Caldes T.

PLoS One. 2018;13(9):e0203885. doi: 10.1371/journal.pone.0203885.

PubMed [citation]

PMID:: 30256826
PMCID:: PMC6157886

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, SCV000275688.7

#	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, SCV000689440.5

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

Description

This missense variant replaces proline with leucine at codon 42 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual meeting the clinical criteria for Lynch Syndrome in the literature (PMID: 30256826). This variant has not been identified 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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