NM_000059.4(BRCA2):c.5946del (p.Ser1982fs) AND Hereditary cancer-predisposing syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Oct 23, 2021
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:: RCV000129627.13

Allele description

NM_000059.4(BRCA2):c.5946del (p.Ser1982fs)

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.5946del (p.Ser1982fs)

Other names:

NP_000050.3:p.Ser1982ArgfsTer22

HGVS:

NC_000013.11:g.32340301del
NG_012772.3:g.29822del
NM_000059.4:c.5946delMANE SELECT
NP_000050.3:p.Ser1982fs
LRG_293:g.29822del
NC_000013.10:g.32914438del
NC_000013.10:g.32914438delT
NM_000059.3:c.5946delT
NM_000059.4:c.5946delT
U43746.1:n.6174delT
c.5946delT
c.5946delT (BIC: 6174delT)
p.S1982Rfs*22
p.S1982RfsX22
p.Ser1982Argfs*22
p.Ser1982ArgfsX22
p.Ser1982fs

Nucleotide change:

6174delT

Protein change:

S1982fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 6174&base_change=del T; Genetic Testing Registry (GTR): GTR000530707; OMIM: 600185.0005; OMIM: 600185.0009; dbSNP: rs80359550

NCBI 1000 Genomes Browser:

rs80359550

Molecular consequence:

NM_000059.4:c.5946del - 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
SCV000184420	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Sep 24, 2021)	germline	clinical testing	PubMed (22) [See all records that cite these PMIDs] 10464624, 14559878, 26440929, 26556299, 26681312, 27836010, 27989354, 28767289, 29084914, 29161300, 29288066, 29321669, 29368341, 29433453, 29492181, 29961768, 29978187, 30274973, 30322717, 31948886, 32338768, 8673091 Citation Link,
SCV000292121	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000679720	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 12, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000787938	True Health Diagnostics	no assertion criteria provided	Pathogenic (Sep 27, 2017)	germline	clinical testing
SCV000996186	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 14, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002536189	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Oct 23, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 9042909, 9150153, 8758903, 10417300, 29446198 Citation Link

Help

Summary from all submissions

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

Citations

PubMed

BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and ovarian cancer.

Schubert EL, Mefford HC, Dann JL, Argonza RH, Hull J, King MC.

Genet Test. 1997;1(1):41-6.

PubMed [citation]

PMID:: 10464624

Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.

Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD.

J Natl Cancer Inst. 2003 Oct 15;95(20):1548-51.

PubMed [citation]

PMID:: 14559878

See all PubMed Citations (28)

Details of each submission

From Ambry Genetics, SCV000184420.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (22)

Description

The c.5946delT pathogenic mutation is located in coding exon 10 of the BRCA2 gene and is one of the well-described Ashkenazi Jewish founder mutations. This mutation results from a deletion of one nucleotide at position 5946, causing a translational frameshift with a predicted alternate stop codon (p.S1982Rfs*22). This mutation has been reported in numerous families affected with breast, ovarian, prostate, pancreatic, and other HBOC-related cancers (Agalliu I et al. Clin. Cancer Res. 2009 Feb;15:1112-20; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84; Lucas AL et al. Clin. Cancer Res. 2013 Jul;19:3396-403; Salo-Mullen EE et al. Cancer. 2015 Dec;121:4382-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Another study indicated that carriers of the c.5946delT mutation may have a lower relative risk for breast cancer when compared to carriers of other non-Ashkenazi Jewish BRCA2 mutations (Finkelman BS et al. J. Clin. Oncol. 2012 Apr;30:1321-8). This mutation is also designated as 6174delT 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000292121.4

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

Description

This variant (also known as 6174delT) deletes 1 nucleotide in exon 11 of the BRCA2 gene, causing a frameshift and a premature translational stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.6-1.52% minor allele frequency (PMID: 30152102). This variant has been reported in numerous individuals affected with breast and ovarian cancer in Ashkenazi Jewish population (PMID: 8673092, 9042909, 9150153, 15994883, 22430266, 30152102), as well as in non-Ashkenazi Jewish population. The risk of female breast cancer among carriers of this mutation is 43-55% by age 70, and the risk of ovarian cancer is 18-37% by age 70 (PMID: 9145676, 15994883, 22430266). This variant has been identified in 78/282088 chromosomes in the general population (61/10364 Ashkenazi Jewish chromosomes) by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. 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 Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV000679720.1

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

#	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 True Health Diagnostics, SCV000787938.1

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

#	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996186.1

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

Description

This variant is also known as c.6174delT using alternate nomenclature. This variant is known as a founder mutation in the Ashkenazi Jewish population (PMID: 20301425) and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 2644092, 29321669, 28767289). Based on the available evidence, the c.5946delT (p.Ser1982ArgfsTer22) variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Sema4, Sema4, SCV002536189.1

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

#	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: Aug 26, 2023

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