NM_000059.4(BRCA2):c.7251_7252del (p.His2417fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 23, 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:: RCV000166921.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.7251_7252del (p.His2417fs)]

NM_000059.4(BRCA2):c.7251_7252del (p.His2417fs)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.7251_7252del (p.His2417fs)

HGVS:

NC_000013.11:g.32355102CA[1]
NG_012772.3:g.44623CA[1]
NM_000059.4:c.7251_7252delMANE SELECT
NP_000050.3:p.His2417fs
LRG_293:g.44623CA[1]
NC_000013.10:g.32929239CA[1]
NC_000013.10:g.32929239_32929240del
NM_000059.3:c.7251_7252delCA
NM_000059.4:c.7251_7252del
p.H2417QFS*3

Nucleotide change:

7479delCA

Protein change:

H2417fs

Links:

dbSNP: rs397507907

NCBI 1000 Genomes Browser:

rs397507907

Molecular consequence:

NM_000059.4:c.7251_7252del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000217740	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000905021	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15131399, 25330149, 25948282, 29446198, 31209999, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000217740

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 17, 2022)

germline

clinical testing

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

Citation Link,

SCV000905021

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2022)

germline

clinical testing

PubMed (6)
[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

Cancer variation associated with the position of the mutation in the BRCA2 gene.

Lubinski J, Phelan CM, Ghadirian P, Lynch HT, Garber J, Weber B, Tung N, Horsman D, Isaacs C, Monteiro AN, Sun P, Narod SA.

Fam Cancer. 2004;3(1):1-10.

PubMed [citation]

PMID:: 15131399

Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland.

Cybulski C, Lubiński J, Wokołorczyk D, Kuźniak W, Kashyap A, Sopik V, Huzarski T, Gronwald J, Byrski T, Szwiec M, Jakubowska A, Górski B, Dębniak T, Narod SA, Akbari MR.

Clin Genet. 2015 Oct;88(4):366-70. doi: 10.1111/cge.12524. Epub 2014 Nov 13.

PubMed [citation]

PMID:: 25330149

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000217740.7

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

Description

The c.7251_7252delCA pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7251 to 7252, causing a translational frameshift with a predicted alternate stop codon (p.H2417Qfs*3). This alteration has been identified in individuals with hereditary breast and/or ovarian cancer (Lubinski J, Fam. Cancer 2004; 3(1):1-10; Kluska A et al. BMC Med Genomics 2015 May;8:19; Cybulski C et al. Clin. Genet. 2015 Oct;88(4):366-70). Of note, this alteration is also designated as 7479delCA and c.7249delCA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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, SCV000905021.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant deletes 2 nucleotides in exon 14 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 7479delCA, c.7249delCA, and c.7249_7250delCA in the literature. This variant has been reported in individuals affected with breast cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 15131399, 25330149, 25948282, 31209999). This variant has also been identified in two families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as 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: Nov 3, 2024

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