NM_004360.5(CDH1):c.337A>G (p.Lys113Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 26, 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:: RCV000572873.9

Allele description [Variation Report for NM_004360.5(CDH1):c.337A>G (p.Lys113Glu)]

NM_004360.5(CDH1):c.337A>G (p.Lys113Glu)

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.337A>G (p.Lys113Glu)

HGVS:

NC_000016.10:g.68801843A>G
NG_008021.1:g.69552A>G
NM_001317184.2:c.337A>G
NM_001317185.2:c.-1279A>G
NM_001317186.2:c.-1483A>G
NM_004360.5:c.337A>GMANE SELECT
NP_001304113.1:p.Lys113Glu
NP_004351.1:p.Lys113Glu
LRG_301t1:c.337A>G
LRG_301:g.69552A>G
NC_000016.9:g.68835746A>G
NM_004360.3:c.337A>G
NM_004360.4:c.337A>G

Protein change:

K113E

Links:

dbSNP: rs876661106

NCBI 1000 Genomes Browser:

rs876661106

Molecular consequence:

NM_001317185.2:c.-1279A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1483A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.337A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.337A>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000669001	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Apr 26, 2024)	germline	clinical testing	Citation Link,
SCV001340256	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23197654, 30661051, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669001

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Apr 26, 2024)

germline

clinical testing

Citation Link,

SCV001340256

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 13, 2022)

germline

clinical testing

PubMed (3)
[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

Identification of germline mutations in the cancer predisposing gene CDH1 in patients with orofacial clefts.

Vogelaar IP, Figueiredo J, van Rooij IA, Simões-Correia J, van der Post RS, Melo S, Seruca R, Carels CE, Ligtenberg MJ, Hoogerbrugge N.

Hum Mol Genet. 2013 Mar 1;22(5):919-26. doi: 10.1093/hmg/dds497. Epub 2012 Nov 29.

PubMed [citation]

PMID:: 23197654

Clinical spectrum and pleiotropic nature of CDH1 germline mutations.

Figueiredo J, Melo S, Carneiro P, Moreira AM, Fernandes MS, Ribeiro AS, Guilford P, Paredes J, Seruca R.

J Med Genet. 2019 Apr;56(4):199-208. doi: 10.1136/jmedgenet-2018-105807. Epub 2019 Jan 19. Review.

PubMed [citation]

PMID:: 30661051
PMCID:: PMC6581119

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000669001.6

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

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, SCV001340256.3

#	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 lysine with glutamic acid at codon 113 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with orofacial cleft (PMID: 23197654, 30661051) and in a patient with endometrial cancer that also harbored a mutation in MSH6 (c.2569_2572del, p.Asp857Phefs*10, PMID: 26517685). This variant has been identified in 1/251152 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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