Submissions for variant NM_000059.4(BRCA2):c.5909C>A (p.Ser1970Ter)

dbSNP: rs80358824

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031588	SCV000282417	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000257911	SCV000072804	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000131108	SCV000186038	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255943	SCV000296535	pathogenic	not provided	2016-04-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000255943	SCV000321471	pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031588	SCV000327307	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000257911	SCV000588106	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131108	SCV000683741	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-31	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000257911	SCV000694916	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-11	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000031588	SCV000786116	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-27	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000031588	SCV001422585	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-01-29	criteria provided, single submitter	curation	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).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031588	SCV001434853	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-02-21	criteria provided, single submitter	clinical testing	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000255943	SCV001449877	pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460519	SCV004216071	pathogenic	Familial cancer of breast	2023-06-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031588	SCV000054194	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031588	SCV000146729	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031588	SCV000212023	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000257911	SCV000587810	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354008	SCV000592013	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735577	SCV000863715	pathogenic	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing