Submissions for variant NM_000059.4(BRCA2):c.8878C>T (p.Gln2960Ter)

dbSNP: rs80359140

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077455	SCV000282462	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045646	SCV000073659	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2960*) 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 breast and/or ovarian cancer (PMID: 10449599, 14531499, 16764716, 18821011, 24312913, 25863477, 26852130). This variant is also known as 9106C>T. ClinVar contains an entry for this variant (Variation ID: 52694). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077455	SCV000196020	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162940	SCV000213427	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-02	criteria provided, single submitter	clinical testing	The p.Q2960* pathogenic mutation (also known as c.8878C>T), located in coding exon 21 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8878. This changes the amino acid from a glutamine to a stop codon within coding exon 21. This mutation has been identified in multiple families with hereditary breast and ovarian cancer syndrome (Santarosa M et al. Int. J. Cancer. 1999 Sep;83:5-9; Miolo G et al. BMC Cancer. 2006 Jun;6:156; Manoukian S et al. Eur. J. Cancer 2007 Feb;43:601-6; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422). 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.
GeneDx	RCV000223154	SCV000278883	pathogenic	not provided	2020-10-13	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 (Santarosa 1999, Fruscalzo 2006, Miolo 2006, Manoukian 2007, Barber 2013, Safra 2013); Not observed 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 9106C>T; This variant is associated with the following publications: (PMID: 29907814, 18821011, 23165508, 26733283, 24131973, 27528623, 26852130, 29161300, 30606148, 25525159, 16764716, 26360800, 25341009, 10449599, 25863477, 24312913, 14531499, 17224268, 16982466, 28263838, 28091860, 29339979, 29446198, 28176296, 30702160, 31825140, 30787465, 30613976)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077455	SCV000327982	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077455	SCV000488176	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000223154	SCV000600828	pathogenic	not provided	2020-09-22	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. It has been reported in hereditary breast and/or ovarian cancer in the published literature (PMIDs: 27425403 (2016), 26852130 (2016), 25863477 (2015), 24312913 (2013), 23165508 (2013), 18821011 (2009), 17224268 (2007), 16982466 (2006), 16764716 (2006), 14531499 (2003), 10449599 (1999), 28091860 (2017), 29161300 (2017), 29339979 (2018), 29446198 (2018), 30606148 (2019), and 30702160 (2019)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic.
Department of Medical Genetics, Oslo University Hospital	RCV000077455	SCV000605642	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162940	SCV000684004	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 22 of the BRCA2 gene, creating a premature translation stop signal. This variant is also known as 9106C>T in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 10 individuals affected with breast or ovarian cancer (PMID: 16982466, 17224268, 23165508, 28091860, 30606148, 32438681, 33471991, 35281878) and has been identified in 38 families among the CIMBA participants (PMID: 29446198). 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	RCV000045646	SCV000695185	pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-05	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.8878C>T (p.Gln2960X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.8902_8913delinsTCCC, p.Thr2968fsX47; c.8904delC, p.Val2969fsX7; c.8930delA, p.Tyr2977fsX11; c.8961_8964delGAGT, p.Ser2988fsX12). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120540 control chromosomes. This variant was reported in multiple individuals affected with HBOC with clear segregation with the disease (Aretini, 2003; Santarosa, 1999; Miolo, 2006) The vaiant is suspected to be a founder mutation in Italian population (Miolo, 2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000045646	SCV000838887	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000223154	SCV001450053	pathogenic	not provided	2019-04-17	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310187	SCV001499782	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473426	SCV004211829	pathogenic	Familial cancer of breast	2023-10-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077455	SCV000109253	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-01-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077455	SCV000147480	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045646	SCV000587974	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077455	SCV002588929	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing