Submissions for variant NM_000059.4(BRCA2):c.9275A>G (p.Tyr3092Cys)

gnomAD frequency: 0.00005  dbSNP: rs80359195

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084297	SCV000073787	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131684	SCV000186720	likely benign	Hereditary cancer-predisposing syndrome	2018-11-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000077466	SCV000221030	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-15	criteria provided, single submitter	literature only
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000077466	SCV000267234	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000586462	SCV000512396	likely benign	not provided	2021-04-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31131967, 32438681, 17924331, 21990134, 19043619, 22505045, 25782689, 10717622, 23108138, 19471317, 21120943, 24916970, 29394989, 18284688, 30040829, 25348012, 12427538, 29625052, 29884841, 32806537)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000424310	SCV000602842	likely benign	not specified	2019-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131684	SCV000684046	likely benign	Hereditary cancer-predisposing syndrome	2016-09-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000424310	SCV000695231	likely benign	not specified	2022-10-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9275A>G (p.Tyr3092Cys) results in a non-conservative amino acid change located in the OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250758 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8e-05 vs 0.00075), allowing no conclusion about variant significance. c.9275A>G has been reported in the literature in individuals suspected of or affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (e.g. Lee_2008, Caux-Moncoutier_2009, Juwle_2012, Peixoto_2014, Kowalik_2018, Santonocito_2020, Park_2021). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.6275_6276delTT, p.Leu2092ProfsX7), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These studies found that the variant has no impact on splicing and has normal HDR activity (e.g. Caux-Moncoutier_2009, Houdayer_2012, Guidugli_2012). Eleven submitters have provided assessments for this variant to ClinVar after 2014. The majority classified the variant as either benign (n=1) or likely benign (n=8) and two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077466	SCV000744561	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586462	SCV001133973	likely benign	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000077466	SCV001139255	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001084297	SCV002025872	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077466	SCV000109264	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077466	SCV000147597	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586462	SCV000592272	likely benign	not provided		no assertion criteria provided	clinical testing	 The BRCA2 p.Tyr3092Cys variant was identified in 3 of 7064 proband chromosomes (frequency: 0.0004) from Portugese, French and American individuals or families with (hereditary) breast and ovarian cancer (Peixoto 2015, Lee 2008 , Malone 2000, Caux-Moncoutier 2011). Functional assays looking at allelic imbalance, homologous directed DNA repair (HDR) and splicing of the variant did not show any defects and the variant was classified as likely not pathogenic (Caux-Moncoutier 2009, Guidugli 2013, Houdayer 2012). In silico models (protein likelihood ratio and multifactorial probability) also classify the variant as neutral/likely benign (Karchin 2008, Lindor 2012, Easton 2007). The variant is reported in ClinVar (Conflicting interpretations of pathogenicity. Benign by Mendelics in 2019. Likely benign by Counsyl in 2015, Integrated Genetics in 2017, GeneDx in 2017, Invitae in 2019, ARUP Laboratories in 2019, Quest Diagnostics in 2019, Ambry in 2018, Color in 2016, SCRP in 2012, Foulkes Cancer Genetics LDI in 2010. Uncertain significance by BIC in 2004, Erasmus Medical Unit in 2015, PLM at Sinai Health System in 2015, Genome Diagnostics Laboratory at Utrecht Universitiy Medical Cenre in 2014, Soonchunhyang University Bucheon Hospital in 2016), LOVD 2.0 (20 entries, 16x VUS, 1x LB, 1x B), ARUP laboratories (2 - Likely not pathogenic or of little clinical significance) databases. The variant was identified in dbSNP (rs80359195) as Uncertain significance. The variant was identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 20 of 281996 chromosomes at a frequency of 0.00007092 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 5 of 30528 chromosomes (freq: 0.000164), Latino in 5 of 35332 chromosomes (freq: 0.000142), Other in 1 of 7194 chromosomes (freq: 0.000139), European (non-Finnish) in 8 of 128648 chromosomes (freq: 0.000062), East Asian in 1 of 19938 chromosomes (freq: 0.00005), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. UMD reports the variant to co-occur with a pathogenic BRCA2 variant, c.6275_6276delTT (p.Leu2092ProfsX7) (from Integrated Genetics ClinVar blurb, SCV000695231.1). The p.Tyr3092 residue is conserved in mammals and more distantly related organisms, and 8 out of 8 computational predictors (MUT Assesor, SIFT, Polyphen2, MT, FATHMM, DANN, MetaLR, Revel) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, the clinical significance of this variant cannot be determined at this time, though we would lean toward a more benign role for this variant. This variant is classified as likely benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735623	SCV000863761	likely benign	Breast and/or ovarian cancer	2010-04-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537212	SCV004747710	likely benign	BRCA2-related disorder	2019-04-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).