rs80358824

Positions:

• chr13-32340264-C-A
• chr13-32340264-C-G
• chr13-32340264-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.5909C>A​(p.Ser1970Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,696 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S1970S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: 0.0530

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32340264-C-A is Pathogenic according to our data. Variant chr13-32340264-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 38007.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340264-C-A is described in Lovd as [Pathogenic]. Variant chr13-32340264-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5909C>A	p.Ser1970Ter	stop_gained	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5909C>A	p.Ser1970Ter	stop_gained	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461696 Hom.: 0 Cov.: 46 AF XY: 0.00000688 AC XY: 5 AN XY: 727152

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000353 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
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	Sharing Clinical Reports Project (SCRP)	Jan 10, 2012	- -
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, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	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 breast and/or ovarian cancer (PMID: 8988179,10359546, 11844822, 14672397, 19329713, 21120943, 24728189, 25682074, 27153395, 27469594), and prostate cancer (PMID: 24556621). This variant has not been identified 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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 29, 2020	The p.Ser1970Ter variant in BRCA2 has been reported in at least 11 individuals with breast or ovarian cancer, including at least 6 individuals with a family history of that cancer (PMID: 14672397, 11844822, 10359546, 27469594, 25682074, 23754601, 27153395, 8988179, 24728189), at least 2 male individuals with prostate cancer (PMID: 20736950, 24556621), and 2 individuals with a family history of cancer (PMID: 19329713), and was absent from large population studies. This variant has also been reported pathogenic in ClinVar (Variation ID: 38007). This nonsense variant leads to a premature termination codon at position 1970, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary susceptibility to breast and ovarian cancer. In summary, this variant meets criteria to be classified as pathogenic for hereditary susceptibility to breast and ovarian cancer in an autosomal dominant manner based on the predicted impact of the variant, multiple occurrences of the variant in affected individuals, and absence in the general population. ACMG/AMP Criteria applied: PVS1, PS4, PM2 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 21, 2019	This variant in the BRCA2 gene is predicted to result in an early stop codon, and loss of function variants are a known pathogenic mechanism of this gene. This variant has been observed in at least three HBOC families (PMID 8988179, 11844822 and 24556621). Additionally, it has been seen in multiple ovarian cancer cases (PMID 24728189), early onset breast cancer (PMID 27469594), and triple negative breast cancer (PMID 25682074). This variant has not been observed in the population database gnomAD, and was absent from specific study controls (PMID 24728189). Therefore, the c.5909C>A (p.Ser1970*) variant in the BRCA2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 27, 2018	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Ser1970*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer and prostate cancer (PMID: 8988179, 20736950, 21120943, 24556621, 24728189, 25682074, 27225819, 27469594). This variant is also known as 6137C>A. ClinVar contains an entry for this variant (Variation ID: 38007). 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	Aug 11, 2023	Variant summary: BRCA2 c.5909C>A (p.Ser1970X) 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 was absent in 250902 control chromosomes. c.5909C>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10359546, 8988179, 20736950, 11844822, 14672397, 24556621, 23754601). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Ser1970X (c.5682C>A) variant in BRCA2 has been reported in at least 12 individuals with BRCA2-related cancers (Gayther 1997, Edwards 2010, Leongamornlert 2014, Labidi-Galy 2018, BIC database) and was absent from large population studies. This nonsense variant is predicted to lead to a premature termination codon at position 1970, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 38007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gayther 1997, Shih 2002, Al-Mulla 2009, Leongamornlert 2014, Song 2014, Maxwell 2016, Donenberg 2019); 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; Also known as 6137C>A; This variant is associated with the following publications: (PMID: 17688236, 11938448, 20609467, 8988179, 24556621, 21120943, 20736950, 25682074, 19329713, 25525159, 27225819, 10359546, 24728189, 15131399, 11844822, 27153395, 30515680, 33646313, 29084914, 31090900, 29446198, 30787465, 33087929) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 04, 2022	The p.S1970* pathogenic mutation (also known as c.5909C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5909. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been observed in multiple individuals and families with breast and/or ovarian cancers (Leongamornlert D et al. Br. J. Cancer. 2014 Mar;110:1663-72; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Donenberg T et al. Breast Cancer Res. Treat. 2016 Aug;159:131-8; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2018 Jan;16:4; Nones K et al. Ann Oncol, 2019 07;30:1071-1079; Abe T et al. J Clin Oncol, 2019 05;37:1070-1080; Labidi-Galy SI et al. Clin Cancer Res, 2018 01;24:326-333; Caux-Moncoutier V et al. Hum Mutat, 2011 Mar;32:325-34; Al-Mulla F et al. J Clin Pathol, 2009 Apr;62:350-6; Nedelcu R et al. Eur J Hum Genet, 2002 Feb;10:150-2; Peto J et al. J Natl Cancer Inst, 1999 Jun;91:943-9). Of note, this alteration is also designed as 6137C>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	May 31, 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 breast and/or ovarian cancer (PMID: 8988179,10359546, 11844822, 14672397, 19329713, 21120943, 24728189, 25682074, 27153395, 27469594), and prostate cancer (PMID: 24556621). This variant has not been identified 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

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- -

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.Ser1970X variant was identified in 7 of 3852 proband chromosomes (frequency: 0.0018) from individuals or families with breast, ovarian and prostate cancer (Al-Mulla_2008_19329713 , Gayther_1997_8988179, Leongamornlert_2014_24556621, Lubinski_2004_15131399 , Shih_2002_11844822 , Wong-Brown_2015_25682074). The variant was also identified in dbSNP (ID: rs80358824) as “With Pathogenic allele”, ClinVar (as pathogenic, reviewed by expert panel), Clinvitae (5x as pathogenic), GeneInsight-COGR (as pathogenic), LOVD 3.0 (3x as pathogenic), UMD-LSDB (56x as causal), and ARUP Laboratories (as "definitely pathogenic"). The variant was not identified in Cosmic, MutDB, BIC Database, Zhejiang Colon Cancer Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In addition, a UK survival study of 2 groups of men with prostate cancer diagnosed at similar ages, showed that men harbouring deleterious germline BRCA2 mutations had a poorer survival outcome than those who did not carry BRCA2 mutations, with 4.8 vs 8.5 years survival rate (Edwards_2010_20736950). The p.Ser1970X variant leads to a premature stop codon at position 1970 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

Jun 20, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Benign	0.96
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.14	N
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		1.3

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: rs80358824; hg19: chr13-32914401;