NM_004360.5(CDH1):c.377C>T (p.Pro126Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 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:: RCV000163916.15

Allele description [Variation Report for NM_004360.5(CDH1):c.377C>T (p.Pro126Leu)]

NM_004360.5(CDH1):c.377C>T (p.Pro126Leu)

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.377C>T (p.Pro126Leu)

HGVS:

NC_000016.10:g.68801883C>T
NG_008021.1:g.69592C>T
NM_001317184.2:c.377C>T
NM_001317185.2:c.-1239C>T
NM_001317186.2:c.-1443C>T
NM_004360.5:c.377C>TMANE SELECT
NP_001304113.1:p.Pro126Leu
NP_004351.1:p.Pro126Leu
LRG_301t1:c.377C>T
LRG_301:g.69592C>T
NC_000016.9:g.68835786C>T
NM_004360.3:c.377C>T
NM_004360.4:c.377C>T
p.P126L

Protein change:

P126L

Links:

dbSNP: rs746703615

NCBI 1000 Genomes Browser:

rs746703615

Molecular consequence:

NM_001317185.2:c.-1239C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1443C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.377C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.377C>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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PREDICTED: Rattus norvegicus kinesin family member 5C (Kif5c), transcript varian...
PREDICTED: Rattus norvegicus kinesin family member 5C (Kif5c), transcript variant X1, mRNA
gi|2678928732|ref|XM_063283548.1|

Nucleotide
LOC109862366 [Pseudomyrmex gracilis]
LOC109862366 [Pseudomyrmex gracilis]
Gene ID:109862366

Gene
AFULGI_RS09530 [Archaeoglobus fulgidus DSM 8774]
AFULGI_RS09530 [Archaeoglobus fulgidus DSM 8774]
Gene ID:24795468

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214511	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jul 8, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28640387, 31871109, 33471991 Citation Link,
SCV000689531	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 5, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28640387, 31871109, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214511

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jul 8, 2021)

germline

clinical testing

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

Citation Link,

SCV000689531

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 5, 2023)

germline

clinical testing

PubMed (4)
[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

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer.

Ricker CN, Hanna DL, Peng C, Nguyen NT, Stern MC, Schmit SL, Idos GE, Patel R, Tsai S, Ramirez V, Lin S, Shamasunadara V, Barzi A, Lenz HJ, Figueiredo JC.

Cancer. 2017 Oct 1;123(19):3732-3743. doi: 10.1002/cncr.30790. Epub 2017 Jun 22.

PubMed [citation]

PMID:: 28640387
PMCID:: PMC5610604

Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon.

Adedokun B, Zheng Y, Ndom P, Gakwaya A, Makumbi T, Zhou AY, Yoshimatsu TF, Rodriguez A, Madduri RK, Foster IT, Sallam A, Olopade OI, Huo D.

Cancer Epidemiol Biomarkers Prev. 2020 Feb;29(2):359-367. doi: 10.1158/1055-9965.EPI-19-0506. Epub 2019 Dec 23.

PubMed [citation]

PMID:: 31871109
PMCID:: PMC7007381

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000214511.7

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

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, SCV000689531.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces proline with leucine at codon 126 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 breast cancer (PMID: 31871109) and colorectal cancer (PMID: 28640387). In a large breast cancer case-control study, this variant has been reported in 0/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 9/282034 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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