NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 5, 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:: RCV000115832.19

Allele description [Variation Report for NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln)]

NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln)

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.1004G>A (p.Arg335Gln)

Other names:

p.R335Q:CGA>CAA; NM_004360.5(CDH1):c.1004G>A

HGVS:

NC_000016.10:g.68811855G>A
NG_008021.1:g.79564G>A
NM_001317184.2:c.1004G>A
NM_001317185.2:c.-612G>A
NM_001317186.2:c.-816G>A
NM_004360.5:c.1004G>AMANE SELECT
NP_001304113.1:p.Arg335Gln
NP_004351.1:p.Arg335Gln
LRG_301t1:c.1004G>A
LRG_301:g.79564G>A
NC_000016.9:g.68845758G>A
NM_004360.3:c.1004G>A
NM_004360.4:c.1004G>A
p.R335Q

Protein change:

R335Q

Links:

dbSNP: rs373364873

NCBI 1000 Genomes Browser:

rs373364873

Molecular consequence:

NM_001317185.2:c.-612G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-816G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.1004G>A - 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
SCV000185512	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Sep 11, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000684319	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12414534, 12532420, 29212164, 32959997, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185512

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Sep 11, 2020)

germline

clinical testing

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

Citation Link,

SCV000684319

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 5, 2023)

germline

clinical testing

PubMed (5)
[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

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer.

Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Höfler H, Becker KF.

Am J Pathol. 2002 Nov;161(5):1881-91.

PubMed [citation]

PMID:: 12414534
PMCID:: PMC1850763

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000185512.8

#	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, SCV000684319.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with glutamine at codon 335 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with gastric cancer (PMID: 12414534, 12532420), breast cancer (PMID: 32959997), and an individual affected with colorectal cancer (PMID: 29212164). This variant has been identified in 7/282636 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: Jun 23, 2024

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