NM_004360.5(CDH1):c.2572G>C (p.Asp858His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 1, 2024
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:: RCV000130458.14

Allele description [Variation Report for NM_004360.5(CDH1):c.2572G>C (p.Asp858His)]

NM_004360.5(CDH1):c.2572G>C (p.Asp858His)

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.2572G>C (p.Asp858His)

HGVS:

NC_000016.10:g.68833422G>C
NG_008021.1:g.101131G>C
NM_001317184.2:c.2389G>C
NM_001317185.2:c.1024G>C
NM_001317186.2:c.607G>C
NM_004360.5:c.2572G>CMANE SELECT
NP_001304113.1:p.Asp797His
NP_001304114.1:p.Asp342His
NP_001304115.1:p.Asp203His
NP_004351.1:p.Asp858His
LRG_301t1:c.2572G>C
LRG_301:g.101131G>C
NC_000016.9:g.68867325G>C
NM_004360.3:c.2572G>C
NM_004360.4:c.2572G>C
p.D858H

Protein change:

D203H

Links:

dbSNP: rs587782025

NCBI 1000 Genomes Browser:

rs587782025

Molecular consequence:

NM_001317184.2:c.2389G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.1024G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001317186.2:c.607G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.2572G>C - 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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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185323	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 1, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26296696, 26483394 Citation Link,
SCV000684442	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 12, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26483394, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185323

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 1, 2024)

germline

clinical testing

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

Citation Link,

SCV000684442

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 12, 2021)

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

Rescreening for genetic mutations using multi-gene panel testing in patients who previously underwent non-informative genetic screening.

Frey MK, Kim SH, Bassett RY, Martineau J, Dalton E, Chern JY, Blank SV.

Gynecol Oncol. 2015 Nov;139(2):211-5. doi: 10.1016/j.ygyno.2015.08.006. Epub 2015 Aug 18.

PubMed [citation]

PMID:: 26296696

Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients.

Hu C, Hart SN, Bamlet WR, Moore RM, Nandakumar K, Eckloff BW, Lee YK, Petersen GM, McWilliams RR, Couch FJ.

Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):207-11. doi: 10.1158/1055-9965.EPI-15-0455. Epub 2015 Oct 19.

PubMed [citation]

PMID:: 26483394
PMCID:: PMC4754121

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000185323.9

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

Description

The p.D858H variant (also known as c.2572G>C), located in coding exon 16 of the CDH1 gene, results from a G to C substitution at nucleotide position 2572. The aspartic acid at codon 858 is replaced by histidine, an amino acid with similar properties. This alteration was previously reported in 1/96 individuals with pancreatic ductal adenocarcinoma via multi-gene cancer panel, who were unselected for family history. This individual was noted to have a family history of endometrial cancer, but no family history of breast or pancreatic cancer (Hu C et al. Cancer Epidemiol. Biomarkers Prev., 2016 Jan;25:207-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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, SCV000684442.5

#	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 aspartic acid with histidine at codon 858 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been reported in an individual affected with pancreatic cancer (PMID: 26483394). This variant has been identified in 2/251486 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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