NM_000059.4(BRCA2):c.2538A>C (p.Ser846=) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Benign (3 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000167797.26

Allele description [Variation Report for NM_000059.4(BRCA2):c.2538A>C (p.Ser846=)]

NM_000059.4(BRCA2):c.2538A>C (p.Ser846=)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.2538A>C (p.Ser846=)

Other names:

2766A>C; p.S846S:TCA>TCC; NP_000050.3:p.Ser846=

HGVS:

NC_000013.11:g.32336893A>C
NG_012772.3:g.26414A>C
NM_000059.4:c.2538A>CMANE SELECT
NP_000050.2:p.Ser846=
NP_000050.3:p.Ser846=
LRG_293t1:c.2538A>C
LRG_293:g.26414A>C
LRG_293p1:p.Ser846=
NC_000013.10:g.32911030A>C
NM_000059.3:c.2538A>C
NM_000059.4:c.2538A>C
U43746.1:n.2766A>C
p.S846S

Links:

Breast Cancer Information Core (BIC) (BRCA2): 2766&base_change=A to C; dbSNP: rs11571654

NCBI 1000 Genomes Browser:

rs11571654

Molecular consequence:

NM_000059.4:c.2538A>C - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000072024	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000494432	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Aug 24, 2015)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21120943, 19656415, 22977638, 24337145 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002026078	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Nov 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000072024

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Benign
(Jan 31, 2024)

germline

clinical testing

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

SCV000494432

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Aug 24, 2015)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV002026078

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Nov 16, 2021)

germline

clinical testing

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

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	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients.

Caux-Moncoutier V, Castéra L, Tirapo C, Michaux D, Rémon MA, Laugé A, Rouleau E, De Pauw A, Buecher B, Gauthier-Villars M, Viovy JL, Stoppa-Lyonnet D, Houdayer C.

Hum Mutat. 2011 Mar;32(3):325-34. doi: 10.1002/humu.21414. Epub 2011 Feb 8.

PubMed [citation]

PMID:: 21120943

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000072024.15

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000494432.2

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

Description

Variant Summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with Mutation Taster predicting the variant to be a "polymorphism." 3/5 in silico programs via Alamut predict no significant effect on splicing and the removal of an ESE binding site, SRp40, although these predictions have yet to be functionally assessed. The variant of interest was observed in a large, broad control population, ExAC with an allele frequency of 98/120626 (1/1231, including 2 homozygotes), which exceeds the maximum expected allele frequency for a BRCA2 variant of 1/1333. The variant of interest has been reported in affected individuals via publications, including a reported co-occurrence with another pathogenic BRCA1 variant (5404delG; De Silva et al 2001). In addition, multiple reputable databases/clinical laboratories (BIC, GeneDx, Ambry Genetics, and Invitae) cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as benign.

#	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 National Health Laboratory Service, Universitas Academic Hospital and University of the Free State, SCV002026078.1

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

Last Updated: Nov 10, 2024

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