NM_004360.5(CDH1):c.2375T>C (p.Met792Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 27, 2022
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:: RCV000566576.8

Allele description [Variation Report for NM_004360.5(CDH1):c.2375T>C (p.Met792Thr)]

NM_004360.5(CDH1):c.2375T>C (p.Met792Thr)

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.2375T>C (p.Met792Thr)

HGVS:

NC_000016.10:g.68829733T>C
NG_008021.1:g.97442T>C
NM_001317184.2:c.2192T>C
NM_001317185.2:c.827T>C
NM_001317186.2:c.410T>C
NM_004360.5:c.2375T>CMANE SELECT
NP_001304113.1:p.Met731Thr
NP_001304114.1:p.Met276Thr
NP_001304115.1:p.Met137Thr
NP_004351.1:p.Met792Thr
LRG_301t1:c.2375T>C
LRG_301:g.97442T>C
NC_000016.9:g.68863636T>C
NM_004360.3:c.2375T>C
NM_004360.4:c.2375T>C

Protein change:

M137T

Links:

dbSNP: rs752349229

NCBI 1000 Genomes Browser:

rs752349229

Molecular consequence:

NM_001317184.2:c.2192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.827T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001317186.2:c.410T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.2375T>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

Recent activity

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LIPE lipase E, hormone sensitive type [Bos taurus]
LIPE lipase E, hormone sensitive type [Bos taurus]
Gene ID:286879

Gene
286879[uid] AND (alive[prop]) (1)
Gene
Synthetic construct Homo sapiens clone IMAGE:100064151, MGC:193234 SRY (sex dete...
Synthetic construct Homo sapiens clone IMAGE:100064151, MGC:193234 SRY (sex determining region Y)-box 11 (SOX11) mRNA, encodes complete protein
gi|182888122|gb|BC160119.1|

Nucleotide
Micromonas pusilla strain RCC2311 18S ribosomal RNA gene, partial sequence
Micromonas pusilla strain RCC2311 18S ribosomal RNA gene, partial sequence
gi|959096213|gb|KT860752.1|

Nucleotide
Thermodesulfobacterium sp. CIR29812 16S ribosomal RNA gene, partial sequence
Thermodesulfobacterium sp. CIR29812 16S ribosomal RNA gene, partial sequence
gi|15788229|gb|AF393376.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000666306	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000908768	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000666306

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 27, 2022)

germline

clinical testing

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

Citation Link,

SCV000908768

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 1, 2020)

germline

clinical testing

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

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

Racial and Ethnic Disparities in Genetic Testing at a Hereditary Breast and Ovarian Cancer Center.

Chapman-Davis E, Zhou ZN, Fields JC, Frey MK, Jordan B, Sapra KJ, Chatterjee-Paer S, Carlson AD, Holcomb KM.

J Gen Intern Med. 2021 Jan;36(1):35-42. doi: 10.1007/s11606-020-06064-x. Epub 2020 Jul 27.

PubMed [citation]

PMID:: 32720237
PMCID:: PMC7859010

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000666306.5

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

Description

The p.M792T variant (also known as c.2375T>C), located in coding exon 15 of the CDH1 gene, results from a T to C substitution at nucleotide position 2375. The methionine at codon 792 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a white female referred for evaluation due to personal and/or family history of cancer (Chapman-Davis E et al. J Gen Intern Med, 2021 01;36:35-42). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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, SCV000908768.3

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

Description

This missense variant replaces methionine with threonine at codon 792 of the CDH1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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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