Submissions for variant NM_000059.4(BRCA2):c.10121C>T (p.Thr3374Ile)

gnomAD frequency: 0.00059  dbSNP: rs56309455

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077246	SCV001161576	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00237 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167783	SCV000071731	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131153	SCV000186095	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.
GeneDx	RCV001719789	SCV000210698	likely benign	not provided	2021-04-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 23415752, 12442275, 18284688, 25348012, 15001988, 15889636, 27621404, 27527004, 28526081, 30254663, 31131967)
Eurofins Ntd Llc (ga)	RCV000120375	SCV000334634	likely benign	not specified	2015-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131153	SCV000683395	likely benign	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001719789	SCV001471441	likely benign	not provided	2020-06-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120375	SCV002066993	likely benign	not specified	2021-06-18	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167783	SCV002515172	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131153	SCV002533192	benign	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492343	SCV004240285	likely benign	Breast and/or ovarian cancer	2022-12-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077246	SCV004846268	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing
ITMI	RCV000120375	SCV000084527	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077246	SCV000109043	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2007-12-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077246	SCV000145757	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077246	SCV000189908	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077246	SCV000592313	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Thr3374Ile variant was identified in 3 of 2236 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was present in 12 of 1498 control chromosomes (frequency: 0.08) from healthy individuals (Ruiz-Flores 2002, Calderon-Garciduneas 2005, Bodian 2014, Zuntini 2018). The variant was identified in dbSNP (rs56309455) as “with other allele, ClinVar (classified as likely benign by GeneDx, Color, SCRP and 2 other submitters, benign by Invitae, Ambry Genetics and Pathway Genomics and uncertain significance by BIC), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 7x). The variant was identified in control databases in 79 of 282,668 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 59 of 24,960 chromosomes (freq: 0.002), Other in 4 of 7214 chromosomes (freq: 0.0006), Latino in 15 of 35,410 chromosomes (freq: 0.0004), European in 1 of 129,038 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The variant was identified in our laboratory and UMD-LSDB in individuals with co-occurring pathogenic BRIP1 (c.1195G>T, p.Glu399*) and BRCA1 (c.3008_3009delTT p.Phe1003*) variants. The p.Thr3374 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004537185	SCV004756332	likely benign	BRCA2-related disorder	2020-03-09	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).