NM_004360.5(CDH1):c.185G>T (p.Gly62Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000167156.6

Allele description [Variation Report for NM_004360.5(CDH1):c.185G>T (p.Gly62Val)]

NM_004360.5(CDH1):c.185G>T (p.Gly62Val)

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.185G>T (p.Gly62Val)

HGVS:

NC_000016.10:g.68801691G>T
NG_008021.1:g.69400G>T
NM_001317184.2:c.185G>T
NM_001317185.2:c.-1431G>T
NM_001317186.2:c.-1635G>T
NM_004360.5:c.185G>TMANE SELECT
NP_001304113.1:p.Gly62Val
NP_004351.1:p.Gly62Val
LRG_301t1:c.185G>T
LRG_301:g.69400G>T
NC_000016.9:g.68835594G>T
NM_004360.3:c.185G>T
NM_004360.4:c.185G>T
p.G62V

Protein change:

G62V

Links:

dbSNP: rs786203727

NCBI 1000 Genomes Browser:

rs786203727

Molecular consequence:

NM_001317185.2:c.-1431G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1635G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.185G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.185G>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
SCV000217987	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 23, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10357799, 17545690, 21777349, 25180051, 30287823 Citation Link,
SCV004360438	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 23, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10357799, 25180051, 30287823, 32426482, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000217987

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 23, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV004360438

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 23, 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

Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer.

Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, Suriano G, Zaor S, Van Manen L, Gilpin C, Nikkel S, Connolly-Wilson M, Weissman S, Rubinstein WS, Sebold C, Greenstein R, Stroop J, Yim D, Panzini B, McKinnon W, Greenblatt M, Wirtzfeld D, et al.

JAMA. 2007 Jun 6;297(21):2360-72. Epub 2007 Jun 3.

PubMed [citation]

PMID:: 17545690

Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population.

Yamada H, Shinmura K, Ito H, Kasami M, Sasaki N, Shima H, Ikeda M, Tao H, Goto M, Ozawa T, Tsuneyoshi T, Tanioka F, Sugimura H.

Cancer Sci. 2011 Oct;102(10):1782-8. doi: 10.1111/j.1349-7006.2011.02038.x. Epub 2011 Aug 19.

PubMed [citation]

PMID:: 21777349

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000217987.8

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

Description

The p.G62V variant (also known as c.185G>T), located in coding exon 3 of the CDH1 gene, results from a G to T substitution at nucleotide position 185. The glycine at codon 62 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in one Japanese male who was diagnosed with diffuse gastric cancer at age 61; he reported having three brothers diagnosed with gastric cancer and both parents diagnosed with gastric cancer (Shinmura K et al, Carcinogenesis 1999 Jun; 20(6):1127-31). This alteration has also been reported in a Brazilian family, wherein both a father and son were diagnosed with diffuse gastric cancer at ages 36 and 31; another daughter was diagnosed with diffuse gastric cancer at 37 and was not tested. Further, testing of tumor cells for the father revealed negative immunoreactivity to the E-cadherin protein (Moreira-Nunes CA et al, Hered Cancer Clin Pract 2014 ; 12(1):18). This alteration was observed in 14/7051 unselected female breast cancer patients; however it was also observed in 48/11241 female controls and 43/12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV004360438.1

#	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 glycine with valine at codon 62 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with diffuse gastric cancer and breast cancer (PMID: 10357799, 25180051, 30287823, 32426482), but also in unaffected individuals (PMID: 30287823, 32426482). 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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