NM_000059.4(BRCA2):c.2612C>A (p.Ser871Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 6, 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:: RCV000213349.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.2612C>A (p.Ser871Ter)]

NM_000059.4(BRCA2):c.2612C>A (p.Ser871Ter)

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.2612C>A (p.Ser871Ter)

HGVS:

NC_000013.11:g.32336967C>A
NG_012772.3:g.26488C>A
NM_000059.4:c.2612C>AMANE SELECT
NP_000050.2:p.Ser871Ter
NP_000050.3:p.Ser871Ter
LRG_293t1:c.2612C>A
LRG_293:g.26488C>A
LRG_293p1:p.Ser871Ter
NC_000013.10:g.32911104C>A
NM_000059.3:c.2612C>A

Nucleotide change:

2840C>A

Protein change:

S871*

Links:

dbSNP: rs397507634

NCBI 1000 Genomes Browser:

rs397507634

Molecular consequence:

NM_000059.4:c.2612C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000273386	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26187060, 28993434, 29084914, 29446198 Citation Link,
SCV001734015	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21120943, 28993434, 29084914, 29446198, 31263054, 32341426, 34452747, 25741868
SCV002535510	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Dec 1, 2021)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 21120943, 22762150, 26187060, 28993434, 29084914, 29446198, 32341426 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000273386

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 6, 2023)

germline

clinical testing

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

Citation Link,

SCV001734015

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 15, 2022)

germline

clinical testing

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

SCV002535510

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Dec 1, 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	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer.

Petridis C, Arora I, Shah V, Moss CL, Mera A, Clifford A, Gillett C, Pinder SE, Tomlinson I, Roylance R, Simpson MA, Sawyer EJ.

Cancer Epidemiol Biomarkers Prev. 2019 Jul;28(7):1162-1168. doi: 10.1158/1055-9965.EPI-18-1102.

PubMed [citation]

PMID:: 31263054

Germline mutations in Black patients with ovarian, fallopian tube and primary peritoneal carcinomas.

Somasegar S, Weiss AS, Norquist BM, Khasnavis N, Radke M, Manhardt E, Pennil C, Pennington KP, Eckert MA, Chryplewicz A, Lengyel E, Swisher EM.

Gynecol Oncol. 2021 Oct;163(1):130-133. doi: 10.1016/j.ygyno.2021.08.017. Epub 2021 Aug 24.

PubMed [citation]

PMID:: 34452747

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV000273386.6

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

Description

The p.S871* pathogenic mutation (also known as c.2612C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 2612. This changes the amino acid from a serine to a stop codon within coding exon 10. This alteration has been detected in an ovarian cancer patient in a cohort study of ovarian cancer patients undergoing germline testing for BRCA1 and BRCA2 (Labidi-Galy SI et al. Clin. Cancer Res., 2018 01;24:326-333). This alteration has been reported in multiple breast cancer patients in studies of Asian breast cancer cohorts (Kwong A et al. J. Med. Genet., 2016 Jan;53:15-23; Wen WX et al. J. Med. Genet., 2018 02;55:97-103). This alteration was also identified in a large, worldwide study of BRCA1 and BRCA2 mutation-positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). 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, SCV001734015.2

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

Description

This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 a personal and/or family history of breast and ovarian cancer (PMID: 21120943, 28993434, 29084914, 29446198, 32341426, 34452747) and in a control individual for a lobular breast cancer case-control study (PMID: 31263054). This variant has been identified in 1/31350 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

From Sema4, Sema4, SCV002535510.1

#	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: Nov 3, 2024

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