Submissions for variant NM_000059.4(BRCA2):c.9292T>C (p.Tyr3098His)

gnomAD frequency: 0.00026  dbSNP: rs41293521

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031810	SCV000244493	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000349
Invitae	RCV001083603	SCV000073795	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031810	SCV000196025	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000120370	SCV000210686	likely benign	not specified	2018-01-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163017	SCV000213505	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000031810	SCV000220608	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-08-20	criteria provided, single submitter	literature only
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768642	SCV000324846	likely benign	Breast and/or ovarian cancer	2023-04-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120370	SCV000538492	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Has been reported in 2 families with female breast and ovarian cancer (Serova-Sinilnikova 1997). Has been classified as benign by Akbari 2011 (based on Myriad classification criteria), Bodian 2011 (presence in controls), Guidugli 2014 (functional assay), Lindor 2012 (posterior probability model OR). No functional impact in DNA break repair assay (Guidugli 2013). B/LB by SCRP, GeneDx, Ambry, Counsyl, Invitae; VUS by BIC in ClinVar.
Fulgent Genetics, Fulgent Genetics	RCV000031810	SCV000575724	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163017	SCV000684051	likely benign	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031810	SCV000743364	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-24	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031810	SCV000744562	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755867	SCV000883494	likely benign	not provided	2017-06-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000031810	SCV001139256	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120370	SCV002066152	likely benign	not specified	2021-12-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163017	SCV002532021	likely benign	Hereditary cancer-predisposing syndrome	2020-11-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120370	SCV002551848	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031810	SCV004846153	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031810	SCV000054418	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-09-05	no assertion criteria provided	clinical testing
ITMI	RCV000120370	SCV000084522	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031810	SCV000147602	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353962	SCV000592273	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2, p.Tyr3098His variant was identified in 6 of 5110 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and prostate cancer (Borg 2010, Edwards 2003, Gayther 1999, Serova-Sinilnikova 1997). The variant was also identified in dbSNP (ID: rs41293521) as “other”, Clinvitae database (classified as benign by ClinVar and Invitae; uncertain significance by ClinVar), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic), the ClinVar database (classified as benign by ENIGMA, MMGLUM, Invitae, Ambry Genetics, SCRP; likely benign by CHEO, GeneDx, Consyl; uncertain significance by BIC), GeneInsight COGR database (classified as benign, likely benign or uncertain significance by a clinical laboratories), the BIC database (33x with unknown clinical importance). This variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), the Exome Aggregation Consortium database (August 8th 2016) in 31 of 117284 chromosomes (freq. 0.0003) in the following populations: Latino in 15 of 11252 chromosomes (freq. 0.001), European in 15 of 93796 chromosomes (freq. 0.0002), African in 1 of 10290 chromosomes (freq. 0.0001), but was not seen in Asian, Finnish and other populations. In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.3841C>T (p.Gln1281X), c.1953dup (p.Lys652GlufsX21); c.6405_6409delCTTAA (p.Asn2135LysfsX3)), increasing the likelihood that the p.Tyr3098His variant does not have clinical significance. The variant was also identified by our laboratory in two individuals with breast cancer. The p.Tyr3098 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, several functional studies classified this variant as class 1 (IARC) with probability of being deleterious 1.07×10−5 (Guidugli 2013, Lindor 2012). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120370	SCV001799499	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120370	SCV001905869	benign	not specified		no assertion criteria provided	clinical testing