NM_000059.4(BRCA2):c.5851_5854del (p.Ser1951fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 13, 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:: RCV000131116.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.5851_5854del (p.Ser1951fs)]

NM_000059.4(BRCA2):c.5851_5854del (p.Ser1951fs)

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.5851_5854del (p.Ser1951fs)

Other names:

6076del4

HGVS:

NC_000013.10:g.32914340_32914343del
NC_000013.11:g.32340206_32340209del
NG_012772.3:g.29727_29730del
NM_000059.4:c.5851_5854delMANE SELECT
NP_000050.3:p.Ser1951fs
LRG_293:g.29727_29730del
NC_000013.10:g.32914340_32914343del
NC_000013.10:g.32914343_32914346del
NC_000013.10:g.32914343_32914346del
NC_000013.10:g.32914343_32914346delAGTT
NM_000059.3:c.5851_5854delAGTT
U43746.1:n.6076_6079delGTTA
U43746.1:n.6079_6082delAGTT
p.S1951WFS*11
p.S1951WfsX11
p.Ser1951Trpfs*11
p.Ser1951fs

Nucleotide change:

6079del4

Links:

Breast Cancer Information Core (BIC) (BRCA2): 6076&base_change=del GTTA; Breast Cancer Information Core (BIC) (BRCA2): 6079&base_change=del AGTT; dbSNP: rs80359543

NCBI 1000 Genomes Browser:

rs80359543

Molecular consequence:

NM_000059.4:c.5851_5854del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000186046	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Feb 9, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18821011, 19353265, 19805903, 22752604, 26183948, 26681312, 32854451, 34680387 Citation Link,
SCV000688951	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 13, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 12955716, 18821011, 25186627, 26183948, 27153395, 27882536, 29335924, 29470806, 29487695, 30430080, 32438681, 32854451, 33471991, 34101484, 34680387, 25741868
SCV002536179	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Dec 17, 2021)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 26681312, 22752604, 29335924, 31825140, 32854451, 29084914, 29446198 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186046

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Feb 9, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000688951

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 13, 2023)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

SCV002536179

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Dec 17, 2021)

germline

curation

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

A BRCA2 founder mutation and seven novel deleterious BRCA mutations in southern Chinese women with breast and ovarian cancer.

Kwong A, Wong LP, Wong HN, Law FB, Ng EK, Tang YH, Chan WK, Ho LS, Kwan KH, Poon M, Wong TT, Leung FC, Chan SW, Ying MW, Ma ES, Ford JM.

Breast Cancer Res Treat. 2009 Oct;117(3):683-6. doi: 10.1007/s10549-009-0385-2. Epub 2009 Apr 8. No abstract available.

PubMed [citation]

PMID:: 19353265

BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation.

Vaidyanathan K, Lakhotia S, Ravishankar HM, Tabassum U, Mukherjee G, Somasundaram K.

J Biosci. 2009 Sep;34(3):415-22.

PubMed [citation]

PMID:: 19805903

See all PubMed Citations (23)

Details of each submission

From Ambry Genetics, SCV000186046.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

The c.5851_5854delAGTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5851 to 5854, causing a translational frameshift with a predicted alternate stop codon (p.S1951Wfs*11). This alteration has been reported in multiple breast and/or ovarian cancer families across various ethnicities (Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Vaidyanathan K et al. J. Biosci. 2009 Sep;34:415-22; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Dodova RI et al. BMC Cancer. 2015 Jul;15:523; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333; Jakimovska M et al. Breast Cancer Res. Treat. 2018 Apr;168(3):745-753; Fanale D et al. Cancers (Basel), 2020 Aug;12:; Wessman S et al. Cancers (Basel), 2021 Oct;13:). Of note, this alteration is also designated as 6079_6082delAGTT and 6079delAGTT 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000688951.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

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 reported in individuals affected with breast and ovarian cancer (PMID: 12955716, 18821011, 25186627, 26183948, 27153395, 27882536, 29487695, 29335924, 29470806, 30430080, 32438681, 32854451, 33471991, 34101484, 34680387, DOI: https://doi.org/10.1515/tjb-2019-0424, Leiden Open Variation Database DB-ID BRCA2_002145, Color internal data). 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

From Sema4, Sema4, SCV002536179.1

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

#	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: Apr 20, 2024

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