NM_004360.5(CDH1):c.160A>G (p.Arg54Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 3, 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:: RCV000129074.15

Allele description [Variation Report for NM_004360.5(CDH1):c.160A>G (p.Arg54Gly)]

NM_004360.5(CDH1):c.160A>G (p.Arg54Gly)

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.160A>G (p.Arg54Gly)

Other names:

p.R54G:AGA>GGA; NM_004360.5(CDH1):c.160A>G; p.Arg54Gly

HGVS:

NC_000016.10:g.68738408A>G
NG_008021.1:g.6117A>G
NM_001317184.2:c.160A>G
NM_001317185.2:c.-1456A>G
NM_001317186.2:c.-1660A>G
NM_004360.5:c.160A>GMANE SELECT
NP_001304113.1:p.Arg54Gly
NP_004351.1:p.Arg54Gly
LRG_301t1:c.160A>G
LRG_301:g.6117A>G
NC_000016.9:g.68772311A>G
NM_004360.3:c.160A>G
NM_004360.4:c.160A>G
p.R54G

Protein change:

R54G

Links:

dbSNP: rs587781329

NCBI 1000 Genomes Browser:

rs587781329

Molecular consequence:

NM_001317185.2:c.-1456A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1660A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.160A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.160A>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
SCV000183777	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Dec 21, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25186627, 28202063 Citation Link,
SCV000684368	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28202063, 36436516, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000183777

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Dec 21, 2021)

germline

clinical testing

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

Citation Link,

SCV000684368

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 3, 2023)

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

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

Next-generation sequencing in familial breast cancer patients from Lebanon.

Jalkh N, Chouery E, Haidar Z, Khater C, Atallah D, Ali H, Marafie MJ, Al-Mulla MR, Al-Mulla F, Megarbane A.

BMC Med Genomics. 2017 Feb 15;10(1):8. doi: 10.1186/s12920-017-0244-7.

PubMed [citation]

PMID:: 28202063
PMCID:: PMC5312584

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000183777.8

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

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, SCV000684368.5

#	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 arginine with glycine at codon 54 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 28202063), hereditary diffuse gastric cancer (PMID: 36436516), and unspecified cancer (PMID: 36436516). This variant has also been observed in over ten individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest hereditary diffuse gastric cancer syndrome (Color internal data). This variant has been identified in 5/182668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant does not appear to be associated with disease but additional studies are necessary 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: Oct 13, 2024

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