NM_000059.4(BRCA2):c.3744_3747del (p.Ser1248fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 25, 2023
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:: RCV000131096.20

Allele description [Variation Report for NM_000059.4(BRCA2):c.3744_3747del (p.Ser1248fs)]

NM_000059.4(BRCA2):c.3744_3747del (p.Ser1248fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.3744_3747del (p.Ser1248fs)

Other names:

3972_3975delTGAG

HGVS:

NC_000013.10:g.32912234_32912237del
NC_000013.11:g.32338099_32338102del
NG_012772.3:g.27620_27623del
NM_000059.4:c.3744_3747delMANE SELECT
NP_000050.3:p.Ser1248fs
LRG_293:g.27620_27623del
NC_000013.10:g.32912234_32912237del
NC_000013.10:g.32912236_32912239del
NC_000013.10:g.32912236_32912239del
NC_000013.10:g.32912236_32912239delTGAG
NM_000059.3:c.3744_3747delTGAG
U43746.1:n.3972_3975delTGAG
p.S1248Rfs*10
p.Ser1248Argfs*10

Nucleotide change:

3972del4

Links:

Breast Cancer Information Core (BIC) (BRCA2): 3972&base_change=del TGAG; dbSNP: rs80359403

NCBI 1000 Genomes Browser:

rs80359403

Molecular consequence:

NM_000059.4:c.3744_3747del - 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
SCV000186026	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 14, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15024741, 17851763, 22217648, 28049253, 28205045, 31336956, 34645131 Citation Link,
SCV000683579	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25863477, 26187060, 28205045, 34063308, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186026

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 14, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000683579

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 25, 2023)

germline

clinical testing

PubMed (5)
[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

BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic.

Foretova L, Machackova E, Navratilova M, Pavlu H, Hruba M, Lukesova M, Valik D.

Hum Mutat. 2004 Apr;23(4):397-8.

PubMed [citation]

PMID:: 15024741

The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified.

Li WF, Hu Z, Rao NY, Song CG, Zhang B, Cao MZ, Su FX, Wang YS, He PQ, Di GH, Shen KW, Wu J, Lu JS, Luo JM, Liu XY, Zhou J, Wang L, Zhao L, Liu YB, Yuan WT, Yang L, Shen ZZ, et al.

Breast Cancer Res Treat. 2008 Jul;110(1):99-109. Epub 2007 Sep 13.

PubMed [citation]

PMID:: 17851763

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000186026.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The c.3744_3747delTGAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3744 to 3747, causing a translational frameshift with a predicted alternate stop codon (p.S1248Rfs*10). This alteration has been reported in multiple breast and/or ovarian cancer families (Foretova L et al. Hum. Mutat. 2004 Apr;23:397-8; Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110:99-109; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Song WH et al. J. Korean Med. Sci. 2017 Feb;32:377-381; Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150; Concolino P et al. Int J Mol Sci, 2019 Jul;20:; Bang YJ et al. Cancer Res Treat, 2021 Oct;:). Of note, this alteration is also designated as 3972_3975delTGAG and 3972del4 in published literature. 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, SCV000683579.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant deletes 4 nucleotides in exon 11 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 has been observed in over twenty individuals affected with breast cancer and is known to be a recurrent disease-causing mutation in the Korean population (PMID: 25863477, 26187060, 28205045, 34063308). This variant has been identified in 1/246600 chromosomes 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: Oct 26, 2024

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