NM_000059.4(BRCA2):c.5946del (p.Ser1982fs) AND Breast-ovarian cancer, familial, susceptibility to, 2

Clinical significance:Pathogenic (Last evaluated: Apr 22, 2016)
Review status:3 stars out of maximum of 4 stars
reviewed by expert panel

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Based on:: 23 submissions [Details]
Record status:: current
Accession:: RCV000009910.31

Allele description [Variation Report for NM_000059.4(BRCA2):c.5946del (p.Ser1982fs)]

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:

1312

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000030127	OMIM	no assertion criteria provided	Pathogenic (Dec 21, 1995)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8524414, 8075631
SCV000054198	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Jan 15, 2013)	germline	clinical testing
SCV000146737	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (May 29, 2002)	germline, unknown	clinical testing
SCV000154098	Counsyl	criteria provided, single submitter Counsyl Autosomal Dominant Disease Classification criteria (2015)	Pathogenic (Apr 7, 2014)	unknown	literature only	PubMed (15) [See all records that cite these PMIDs] 15695382, 22006311, 22009639, 20887823, 19188187, 22703879, 23658460, 8673092, 15994883, 8673091, 21324516, 22430266, 9145676, 10570174, 18607349 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000189906	Pathway Genomics	no assertion criteria provided	Pathogenic (Jul 24, 2014)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20301425, 23199084, 15994883, 22430266
SCV000195993	Michigan Medical Genetics Laboratories,University of Michigan	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Nov 3, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000263344	Centro de Genética y Biología Molecular, Universidad de San Martín de Porres - Mutational analysis of BRCA1 and BRCA2 genes in peruvian families with hereditary breast and ovarian cancer	no assertion criteria provided	Pathogenic (Jun 10, 2015)	not applicable	research
SCV000282418	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	reviewed by expert panel ENIGMA BRCA1/2 Classification Criteria (2015)	Pathogenic (Apr 22, 2016)	germline	curation	ENIGMA BRCA1/2 Classification Criteria (2015), Citation Link,
SCV000327312	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	criteria provided, single submitter CIMBA Mutation Classification guidelines May 2016	Pathogenic (Oct 2, 2015)	germline	clinical testing	CIMBA_Mutation_Classification_guidelines_May16.pdf, Citation Link,
SCV000575747	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Feb 12, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000592016	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV000593749	Genetic Services Laboratory,University of Chicago	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (May 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000605651	Department of Medical Genetics, Oslo University Hospital	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Jul 1, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000733276	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000744479	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus	criteria provided, single submitter ACGS Guidelines, 2013	Pathogenic (Sep 21, 2015)	germline	clinical testing	Citation Link,
SCV000803796	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne - Clinvar_gadteam_Clinical_exome_analysis_3	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Nov 7, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000839905	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (May 24, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001478111	Department of Pediatrics,Memorial Sloan Kettering Cancer Center	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Dec 15, 2020)	germline	research	PubMed (2) [See all records that cite these PMIDs] 28873162, 25741868
SCV001934380	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Jan 4, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002570374	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (May 3, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14559878, 15695382, 16825431, 20301425, 29084914, 30152102, 8758903, 25741868
SCV002581177	MGZ Medical Genetics Center	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Aug 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761748	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia,Australian Genomics	criteria provided, single submitter ACMG Guidelines, 2015	Pathogenic (Apr 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002764549	New York Genome Center	criteria provided, single submitter NYGC Assertion Criteria 2020	Pathogenic (Mar 31, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20301425, 29084914, 29433453, 29321669, 28767289 Citation Link

Description

ACMG criteria applied: PVS1, PS4: SCV002581177

Summary from all submissions

Help

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	1312	not provided	2	not provided	clinical testing, curation
not provided	not provided	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	186	not provided	not provided	186	not provided	clinical testing, literature only
not provided	germline	yes	282	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	yes	6	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
Ashkenazi	germline	yes	700	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi Jewish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Central/Eastern European	germline	yes	19	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Central/Eastern European, Italian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Central/Eastern European, Russian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Latin American, Caribbean	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Latin American, Caribbean, Mex	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Western European	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Western, Eastern, Central European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Cacasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Caucasian	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing
Caucasian Non Hispanic	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
Central/Eastern European	germline	yes	12	not provided	not provided	not provided	not provided	clinical testing
Central/Eastern European, Jewish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Central/Eastern European, Russian Polish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Czech, Hungarian, Russian, Jewish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Dutch	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Jewish	germline	yes	13	not provided	not provided	not provided	not provided	clinical testing
Jewish, Polish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Latin American, Caribbean, Western European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Near Eastern Mid East	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European	germline	yes	25	not provided	not provided	not provided	not provided	clinical testing
Western European, Ashkenazi	germline	yes	18	not provided	not provided	not provided	not provided	clinical testing
Western European, Ashkenazi, Central, Eas	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European, Ashkenazi, English	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European, Ashkenazi, French Ca	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European, Ashkenazi, French, Jewish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European, Ashkenazi, Irish, Italian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European, Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European, German, Jewish	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western Europeanan, Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of the breast cancer susceptibility gene BRCA2.

Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G.

Nature. 1995 Dec 21-28;378(6559):789-92. Erratum in: Nature 1996 Feb 22;379(6567):749.

PubMed [citation]

PMID:: 8524414

Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.

Stratton MR, Ford D, Neuhasen S, Seal S, Wooster R, Friedman LS, King MC, Egilsson V, Devilee P, McManus R, et al.

Nat Genet. 1994 May;7(1):103-7.

PubMed [citation]

PMID:: 8075631

See all PubMed Citations (29)

Details of each submission

From OMIM, SCV000030127.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 families from Montreal with breast-ovarian cancer (BROVCA2; 612555), Wooster et al. (1995) found a T deletion and an AAAC deletion (600185.0006), respectively, in the BRCA2 gene. Both of these families included a male breast cancer case; previous analyses had indicated that the large majority of such families have BRCA2 mutations (Stratton et al., 1994).

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

From Sharing Clinical Reports Project (SCRP), SCV000054198.6

#	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	not provided	186	not provided	not provided		not provided	not provided	not provided	See 1

Co-occurrences

#	Zygosity	Alleles	Number of Observations
1	SingleHeterozygote	BRCA2:A227T	2
1	SingleHeterozygote	BRCA1:187delAG	2

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146737.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	185	not provided	not provided	clinical testing	not provided
2	not provided	69	not provided	not provided	clinical testing	not provided
3	not provided	1	not provided	not provided	clinical testing	not provided
4	not provided	1	not provided	not provided	clinical testing	not provided
5	not provided	2	not provided	not provided	clinical testing	not provided
6	not provided	1	not provided	not provided	clinical testing	not provided
7	not provided	2	not provided	not provided	clinical testing	not provided
8	not provided	2	not provided	not provided	clinical testing	not provided
9	not provided	1	not provided	not provided	clinical testing	not provided
10	not provided	1	not provided	not provided	clinical testing	not provided
11	not provided	4	not provided	not provided	clinical testing	not provided
12	not provided	6	not provided	not provided	clinical testing	not provided
13	Ashkenazi	694	not provided	not provided	clinical testing	not provided
14	Ashkenazi	6	not provided	not provided	clinical testing	not provided
15	Ashkenazi Jewish	1	not provided	not provided	clinical testing	not provided
16	Ashkenazi, Central/Eastern European	19	not provided	not provided	clinical testing	not provided
17	Ashkenazi, Central/Eastern European, Italian	1	not provided	not provided	clinical testing	not provided
18	Ashkenazi, Central/Eastern European, Russian	1	not provided	not provided	clinical testing	not provided
19	Ashkenazi, Latin American, Caribbean	1	not provided	not provided	clinical testing	not provided
20	Ashkenazi, Latin American, Caribbean, Mex	1	not provided	not provided	clinical testing	not provided
21	Ashkenazi, Western European	2	not provided	not provided	clinical testing	not provided
22	Ashkenazi, Western, Eastern, Central European	1	not provided	not provided	clinical testing	not provided
23	Asian	1	not provided	not provided	clinical testing	not provided
24	Cacasian	1	not provided	not provided	clinical testing	not provided
25	Caucasian	1	not provided	not provided	clinical testing	not provided
26	Caucasian	2	not provided	not provided	clinical testing	not provided
27	Caucasian	1	not provided	not provided	clinical testing	not provided
28	Caucasian Non Hispanic	3	not provided	not provided	clinical testing	not provided
29	Central/Eastern European	12	not provided	not provided	clinical testing	not provided
30	Central/Eastern European, Jewish	1	not provided	not provided	clinical testing	not provided
31	Central/Eastern European, Russian Polish	1	not provided	not provided	clinical testing	not provided
32	Czech, Hungarian, Russian, Jewish	1	not provided	not provided	clinical testing	not provided
33	Dutch	1	not provided	not provided	clinical testing	not provided
34	Jewish	11	not provided	not provided	clinical testing	not provided
35	Jewish	1	not provided	not provided	clinical testing	not provided
36	Jewish	1	not provided	not provided	clinical testing	not provided
37	Jewish, Polish	1	not provided	not provided	clinical testing	not provided
38	Latin American, Caribbean, Western European	1	not provided	not provided	clinical testing	not provided
39	Near Eastern Mid East	1	not provided	not provided	clinical testing	not provided
40	Western European	25	not provided	not provided	clinical testing	not provided
41	Western European, Ashkenazi	18	not provided	not provided	clinical testing	not provided
42	Western European, Ashkenazi, Central, Eas	1	not provided	not provided	clinical testing	not provided
43	Western European, Ashkenazi, English	1	not provided	not provided	clinical testing	not provided
44	Western European, Ashkenazi, French Ca	1	not provided	not provided	clinical testing	not provided
45	Western European, Ashkenazi, French, Jewish	1	not provided	not provided	clinical testing	not provided
46	Western European, Ashkenazi, Irish, Italian	1	not provided	not provided	clinical testing	not provided
47	Western European, Central/Eastern European	1	not provided	not provided	clinical testing	not provided
48	Western European, German, Jewish	1	not provided	not provided	clinical testing	not provided
49	Western Europeanan, Central/Eastern European	1	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	yes	not provided	not provided	not provided		185	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		69	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
6	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
8	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
9	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
10	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
11	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided
12	unknown	yes	not provided	not provided	not provided		6	not provided	not provided	not provided
13	germline	yes	not provided	not provided	not provided		694	not provided	not provided	not provided
14	germline	yes	not provided	not provided	not provided		6	not provided	not provided	not provided
15	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
16	germline	yes	not provided	not provided	not provided		19	not provided	not provided	not provided
17	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
18	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
19	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
20	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
21	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
22	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
23	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
24	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
25	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
26	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
27	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
28	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided
29	germline	yes	not provided	not provided	not provided		12	not provided	not provided	not provided
30	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
31	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
32	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
33	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
34	germline	yes	not provided	not provided	not provided		11	not provided	not provided	not provided
35	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
36	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
37	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
38	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
39	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
40	germline	yes	not provided	not provided	not provided		25	not provided	not provided	not provided
41	germline	yes	not provided	not provided	not provided		18	not provided	not provided	not provided
42	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
43	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
44	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
45	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
46	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
47	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
48	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
49	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Counsyl, SCV000154098.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	literature only	PubMed (15)

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

From Pathway Genomics, SCV000189906.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	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 Michigan Medical Genetics Laboratories,University of Michigan, SCV000195993.1

#	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	yes	not provided	Blood	not provided		not provided	not provided	not provided	not provided

From Centro de Genética y Biología Molecular, Universidad de San Martín de Porres - Mutational analysis of BRCA1 and BRCA2 genes in peruvian families with hereditary breast and ovarian cancer, SCV000263344.1

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

Description

Phatogenic mutation

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

From Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000282418.1

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

Description

Variant allele predicted to encode a truncated non-functional protein.

#	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 Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000327312.4

#	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	1312	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000575747.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592016.2

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

Description

The BRCA2 p.Ser1982Argfs*22 variant was identified in 33 of 11966 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian and pancreatic cancer (Agalliu 2009, Borg 2010, Couch 2014, Edwards 2010, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359550) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified as pathogenic by 34 submitters including Invitae, GeneDx, Counsyl, ARUP and Ambry Genetics), COGR (3 entries classified as pathogenic), COSMIC (1x confirmed somatic in adenocarcinoma of the pancreas), LOVD 3.0 (110 entries classified as affects function), UMD-LSDB (75 entries classified as causal), BIC Database (1090 entries classified as pathogenic), ARUP Laboratories (classified as definitely pathogenic), and the Zhejiang Colon Cancer Database (classified as pathogenic). The variant was not identified in the MutDB database. The variant was also identified by our laboratory in multiple individuals with breast, ovarian or pancreatic cancer. The variant was identified in control databases in 72 of 276978 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Ashkenazi Jewish in 59 of 10150 chromosomes (freq: 0.006), Other in 3 of 6460 chromosomes (freq: 0.0005), European (Non-Finnish) in 10 of 126512 chromosomes (freq: 0.00008); it was not observed in the African, East Asian, European (Finnish), Latino, or South Asian populations. The c.5946delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1982 and leads to a premature stop codon 22 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. The truncating BRCA2 6174delT Ashkenazi Jewish founder mutation is associated with a breast cancer risk of 70% by age 70 and identified in the vast majority of Ashkenazi Jewish families with a history of breast and ovarian cancer (Pohlreich 2005, Wu 2005). In addition, a functional study using bacterial artificial chromosomes concluded that this mutation could not rescue lethality in BRCA2-deficient mouse embryonic stem cells, supporting its classification as deleterious (Kuznetsov 2008). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. Assessment Date: 2018/03/07.

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

From Genetic Services Laboratory,University of Chicago, SCV000593749.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Medical Genetics, Oslo University Hospital, SCV000605651.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	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	yes	not provided	not provided	not provided		11	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000733276.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV000744479.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne - Clinvar_gadteam_Clinical_exome_analysis_3, SCV000803796.1

#	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	unknown	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839905.1

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

Description

The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic.[leduc, 2017-03-07]

#	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 Department of Pediatrics,Memorial Sloan Kettering Cancer Center, SCV001478111.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001934380.1

#	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV002570374.1

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

Description

This variant (rs28897738) has been reported in the literature in association with a variety of BRCA2-related cancer conditions that are inherited in a dominant or recessive manner. It is known as a founder mutation in the Ashkenazi Jewish population and has also been observed in individuals of non-Ashkenazi Jewish descent. It is rare (<0.1%) in a large population dataset (gnomAD: 78/282088 total alleles; 0.0277%; no homozygotes) and has been reported in ClinVar(Variation ID 9325). This frameshift variant results in a premature stop codon in exon 11, likely leading to nonsense-mediated decay and lack of protein production and has supporting functional evidence. We consider this variant to be 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 MGZ Medical Genetics Center, SCV002581177.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002761748.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center, SCV002764549.1

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

Description

The c.5946del, p.Ser1982ArgfsTer22 missense variant identified in BRCA2, also known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, 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, 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	unknown	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Mar 26, 2023

Relating variation to medicine