rs397507634

Positions:

• chr13-32336967-C-A
• chr13-32336967-C-G
• chr13-32336967-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.2612C>A​(p.Ser871Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 2.46

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32336967-C-A is Pathogenic according to our data. Variant chr13-32336967-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 51315.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32336967-C-A is described in Lovd as [Pathogenic]. Variant chr13-32336967-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2612C>A	p.Ser871Ter	stop_gained	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.2612C>A	p.Ser871Ter	stop_gained	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74286

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 29, 2012	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 06, 2023	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 01, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast and/or ovarian cancer (Coulet et al., 2020; Labidi-Galy et al., 2018; De Talhouet et al., 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2840C>A; This variant is associated with the following publications: (PMID: 25525159, 20858050, 29446198, 32341426, 30720243, 29084914, 34367235, 33858029) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 07, 2022	This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.00011 (1/8706 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and families with hereditary breast and ovarian cancer (PMIDs: 32341426 (2020), 29084914 (2018), 28993434 (2018), 22762150 (2012), 21120943 (2011), 20858050 (2010)). Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2023	This sequence change creates a premature translational stop signal (p.Ser871*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs397507634, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 51315). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2019	Variant summary: BRCA2 c.2612C>A (p.Ser871X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 222380 control chromosomes. c.2612C>A has been reported in the literature in individuals affected or suspected to be affected with Hereditary Breast and Ovarian Cancer (e.g. Coulet_2010, Wen_2017, Labidi-Galy_2018, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other submissions to ClinVar (evaluation after 2014, including one expert panel-ENIGMA) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

May 06, 2019

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2024

The BRCA2 c.2612C>A variant is predicted to result in premature protein termination (p.Ser871*). This variant was reported in multiple individuals with breast and/or ovarian cancer (see examples: De Talhouet et al. 2020. PubMed ID: 32341426, Labidi-Galy et al. 2018. PubMed ID: 29084914, Rebbeck et al. 2018. PubMed ID: 29446198). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic and likely pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51315/). Another nucleotide substitution leading to the same protein truncating variant has been reported in one patient with breast cancer (c.2612C>G, p.Ser871*; Kwong et al. 2016. PubMed ID: 26187060). Nonsense variants in BRCA2 are expected to be pathogenic. The c.2612C>A variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Ser871X variant was not identified in the literature nor was it identified in the GeneInsight-COGR database, COSMIC, the BIC database and the Fanconi Anemia Mutation Database (LOVD). In addition, the variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and in the Exome Aggregation Consortium database (August 8, 2016). The variant was identified in dbSNP (ID: rs397507634) as “With Pathogenic allele”; in the ARUP Laboratories BRCA Mutations Database as definitely pathogenic; in the Clinvitae and Clinvar databases as pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Allelles (Engima) Study description, Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) University of Cambridge, Ambry Genetics, and Sharing Clinical Reports Project. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Ser871X variant leads to a premature stop codon at position 871, which is predicted to lead to 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. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.70	D
MutationTaster	Benign	1.0	A;A
Vest4		0.86
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507634; hg19: chr13-32911104; COSMIC: COSV66461918; COSMIC: COSV66461918;