rs80358815

chr13-32340219-C-Achr13-32340219-C-Gchr13-32340219-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.5864C>A(p.Ser1955Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,790 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: -0.525

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 13-32340219-C-A is Pathogenic according to our data. Variant chr13-32340219-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 51954.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340219-C-A is described in Lovd as [Pathogenic]. Variant chr13-32340219-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5864C>A	p.Ser1955Ter	stop_gained	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5864C>A	p.Ser1955Ter	stop_gained	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250960 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461680 Hom.: 0 Cov.: 46 AF XY: 0.00000413 AC XY: 3 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 28, 2014	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 06, 2012	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 07, 2022	PP5, PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with BRCA2-related cancers (Meindl et al., 2002; Lubinski et al., 2004; Cunningham et al., 2014; Pritchard et al., 2016; Barnes et al., 2018); Also known as 6092C>A; This variant is associated with the following publications: (PMID: 27433846, 11802209, 30787465, 26483394, 24504028, 15131399, 19340607, 26848529, 24728189, 25525159, 27393621, 28324225, 12928470, 26295337, 26586665, 16683254, 29101607, 28476184, 29446198, 30720243, 30702160, 29625052, 26689913, 31825140, 36149077, 32073954, 29922827) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	BRCA2: PVS1, PM2, PP1, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 27, 2020	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2023	Variant summary: BRCA2 c.5864C>A (p.Ser1955X) 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. The variant allele was found at a frequency of 1.2e-05 in 250960 control chromosomes (gnomAD). c.5864C>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (HBOC) Syndrome (e.g. Meindl_2002, de la Hoya_2003, Lubinski_2004, Song_2014, Dorling_2021), and the variant was found to co-segregate with the disease in multiple HBOC families. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11802209, 15131399, 24728189, 12928470, 33471991). 16 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Ser1955*) 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 (rs80358815, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11802209, 15131399, 16683254, 24504028, 24728189, 26483394, 26586665, 27433846). This variant is also known as 6092C>A. ClinVar contains an entry for this variant (Variation ID: 51954). For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Oct 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 02, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2021	The p.S1955* pathogenic mutation (also known as c.5864C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5864. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been reported in multiple high-risk breast and/or ovarian cancer kindreds (Meindl A et al. Int. J. Cancer. 2002 Feb;97(4):472-80; Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238). It has also been reported in a patient with epithelial ovarian cancer and a patient with metastatic prostate cancer, both of whom were unselected for family history of cancer or age at diagnosis (Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Pritchard CC et al. N. Engl. J. Med. 2016 Aug 4;375(5):443-53). Of note, this alteration is also designated as S1955X and 6092C>A 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2021	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast, ovarian, pancreatic and prostate cancer and two unaffected individuals (PMID: 19340607, 24504028, 26483394, 27433846, 33471991; Leiden Open Variation Database DB-ID BRCA2_001762). This variant also has been reported in suspected hereditary breast and ovarian cancer families (PMID: 11802209, 12928470, 15131399, 16683254, 28324225). This variant has been identified in 4/282358 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 23, 2017

- -

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.Ser1955X variant was identified in 3 of 4656 proband chromosomes (frequency: 0.001) from German and multiethnic cohorts of individuals or families with ovarian and breast/other cancers (Meindl 2002, Lubinski 2004). In a study correlating mutation locus to disease risk in BRCA2 positive patients, Lubinski (2004) found that mutations falling within BIC 3035-6629, considered the OCCR (ovarian cancer cluster region), had increased risk of ovarian cancer and decreased risk of breast and prostate cancers compared to nonOCCR regions. In another study assessing HRD (homologous recombination deficiency) in ovarian cancer patients unselected for family history, it was found that patients with germline or somatic mutations in BRCA1, BRCA2 or RAD51C, were likely to have high grade serous tumors, earlier onset diagnosis, and have ovarian/breast cancer within the family (Cunningham 2014). The variant was also identified in dbSNP (ID: rs80358815) “With Pathogenic allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined; HGMD, Clinvitae database (as pathogenic), the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports; in addition to being classified as pathogenic by BIC and Ambry Genetics, likely pathogenic by Counsyl, and classification not provided by Invitae), GeneInsight COGR database (2X, classified as pathogenic and likely pathogenic by 2 clinical laboratories), the BIC database (14X with pathogenic clinical importance), and UMD (1X as a causal variant). The variant was also identified by our laboratory in 1 individual(s) with ovarian cancer.The p.Ser1955X variant leads to a premature stop codon at position 1955, 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	33
Dann	Benign	0.96
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.096	N
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		0.58

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: rs80358815; hg19: chr13-32914356;