Submissions for variant NM_000059.4(BRCA2):c.8917C>T (p.Arg2973Cys)

gnomAD frequency: 0.00003  dbSNP: rs45469092

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)	RCV000031776	SCV000244489	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 = 0.00000178
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086936	SCV000073670	benign	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163016	SCV000213504	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	RCV000031776	SCV000220285	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-05-01	criteria provided, single submitter	literature only
GeneDx	RCV000428227	SCV000512394	benign	not specified	2015-09-03	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.
Department of Pathology and Molecular Medicine, Queen's University	RCV000428227	SCV000588124	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000428227	SCV000602818	benign	not specified	2016-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428227	SCV000695191	benign	not specified	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8917C>T (p.Arg2973Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 249368 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8917C>T has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Lee_2008, Spearman_2008, Lu_2012, Grant_2015, Ricks-Santi_2017, Solodskikh_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been internally reported (BRCA1 c.68_69delAG, p.Glu23fsX17), providing supporting evidence for a benign role. Some functional studies report this variant had no or slight impact on protein function (Farrugia_2008, Guidugli_2017, Mesman_2018). Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (7x) and likely benign (2x). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007, Lindor_2012). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000034469	SCV000805790	likely benign	not provided	2017-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769706	SCV000901125	likely benign	Breast and/or ovarian cancer	2022-02-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163016	SCV000910652	benign	Hereditary cancer-predisposing syndrome	2016-01-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000428227	SCV001133956	benign	not specified	2019-04-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163016	SCV002531987	likely benign	Hereditary cancer-predisposing syndrome	2021-08-26	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034469	SCV005093013	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA2: BS3:Supporting
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034469	SCV000043235	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031776	SCV000054384	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-11-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031776	SCV000147487	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	RCV000034469	SCV001553009	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Arg2973Cys variant was identified in 5 of 3808 proband chromosomes (frequency: 0.001) from individuals or families with breast or pancreatic cancer and was present in 1 of 1144 control chromosomes (frequency: 0.0009) from healthy individuals (Lee 2008, Spearman 2008, Grant 2015, Ricks-Santi 2017). The variant was identified in dbSNP (rs45469092) as “with uncertain significance allele”, ClinVar (classified as benign by Ambry Genetics, GeneDx, ENIGMA, Color and 3 other submitters; as likely benign by Invitae, Counsyl, Prevention Genetics and 2 other submitters; and as uncertain significance by BIC and NIH), LOVD 3.0 (observed 10x) and UMD-LSDB (observed 1x). The variant was identified in control databases in 7 of 280,740 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7162 chromosomes (freq: 0.0001) and European in 6 of 127,866 chromosomes (freq: 0.00005); it was not observed in the African, Latino , Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro expression of the variant demonstrated no effect on homology directed repair activity or induction of centrosome amplification (Farrugia 2008, Guidugli 2013). The variant was reported in ClinVar by another clinical laboratory to have been identified in an individual with a co-occurring pathogenic BRCA1 variant (p.Glu23fs*17), decreasing the likelihood that this variant has clinical significance (Integrated Genetics/Laboratory Corporation of America ClinVar submission dated May 31, 2018). The p.Arg2973 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.