NM_004360.5(CDH1):c.532-1G>C AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Sep 26, 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:: RCV001023925.9

Allele description [Variation Report for NM_004360.5(CDH1):c.532-1G>C]

NM_004360.5(CDH1):c.532-1G>C

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.532-1G>C

HGVS:

NC_000016.10:g.68808692G>C
NG_008021.1:g.76401G>C
NM_001317184.2:c.532-1G>C
NM_001317185.2:c.-1084-1G>C
NM_001317186.2:c.-1288-1G>C
NM_004360.5:c.532-1G>CMANE SELECT
LRG_301t1:c.532-1G>C
LRG_301:g.76401G>C
NC_000016.9:g.68842595G>C
NM_004360.3:c.532-1G>C
NM_004360.4(CDH1):c.532-1G>C

Links:

dbSNP: rs771085839

NCBI 1000 Genomes Browser:

rs771085839

Molecular consequence:

NM_001317184.2:c.532-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001317185.2:c.-1084-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001317186.2:c.-1288-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_004360.5:c.532-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001185869	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 26, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32427313, 34949788 Citation Link,
SCV002529192	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Oct 22, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 32427313, 26556299, 20373070 Citation Link,
SCV004360451	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 31, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26556299, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001185869

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Sep 26, 2024)

germline

clinical testing

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

Citation Link,

SCV002529192

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Oct 22, 2021)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004360451

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 31, 2022)

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, curation

Citations

PubMed

CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer.

Adib E, El Zarif T, Nassar AH, Akl EW, Abou Alaiwi S, Mouhieddine TH, Esplin ED, Hatchell K, Nielsen SM, Rana HQ, Choueiri TK, Kwiatkowski DJ, Sonpavde G.

Br J Cancer. 2022 Mar;126(5):797-803. doi: 10.1038/s41416-021-01673-7. Epub 2021 Dec 23.

PubMed [citation]

PMID:: 34949788
PMCID:: PMC8888603

Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women.

Palmer JR, Polley EC, Hu C, John EM, Haiman C, Hart SN, Gaudet M, Pal T, Anton-Culver H, Trentham-Dietz A, Bernstein L, Ambrosone CB, Bandera EV, Bertrand KA, Bethea TN, Gao C, Gnanaolivu RD, Huang H, Lee KY, LeMarchand L, Na J, Sandler DP, et al.

J Natl Cancer Inst. 2020 Dec 14;112(12):1213-1221. doi: 10.1093/jnci/djaa040. Erratum in: J Natl Cancer Inst. 2020 Oct 1;112(10):1071. doi: 10.1093/jnci/djaa086..

PubMed [citation]

PMID:: 32427313
PMCID:: PMC7735769

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV001185869.6

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

Description

The c.532-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 5 of the CDH1 gene. This alteration was observed in 1 of 5054 African American women with breast cancer (Palmer JR et al. J Natl Cancer Inst, 2020 Dec;112:1213-1221). This alteration was also identified in an individual diagnosed with diffuse gastric cancer and colorectal cancer (Adib E et al. Br J Cancer, 2022 Mar;126:797-803). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

#	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 Sema4, Sema4, SCV002529192.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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, SCV004360451.1

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

Description

This variant causes a G to C nucleotide substitution at the -1 position of intron 4 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with esophagogastric cancer in the literature (PMID: 26556299). This variant has been identified in 1/250964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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: Feb 25, 2025

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