Submissions for variant NM_000059.4(BRCA2):c.7463G>A (p.Arg2488Lys)

gnomAD frequency: 0.00001  dbSNP: rs80358968

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001284108	SCV000210650	likely benign	not provided	2020-05-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25348012, 24817641, 19043619, 19471317, 20858050, 21673748, 22505045, 15026808, 27974384, 31102422, 31131967)
Counsyl	RCV000077401	SCV000488203	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000077401	SCV000575726	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563199	SCV000661177	likely benign	Hereditary cancer-predisposing syndrome	2018-07-23	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.
Color Diagnostics, LLC DBA Color Health	RCV000563199	SCV000689049	likely benign	Hereditary cancer-predisposing syndrome	2017-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168600	SCV000695069	likely benign	not specified	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7463G>A (p.Arg2488Lys) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7463G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer and acute lymphoblastic leukemia (Claes_2004, Caux-Moncoutier_2009, de Smith_2019). Claes_2004 indicated the variant did not segregate with disease for one of the affected families. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, co-occurrences with other pathogenic variants have been reported (BRCA2 c.2745_2746delTT , p.Val917LysfsX18; BRCA1 c.1961dup, p.Tyr655ValfsX18; BRCA1 c.4183C>T, p.Gln1395X; BRCA1 c.IVS21+1G>T , c.5332+1G>T; BRCA1 c.4389C>A , p.Tyr1463X ; BRCA1 442_4357del , p.Glu149TyrfsX2, in UMD database), providing supporting evidence for a benign role. Although the variant is not located in a commonly known location to affect splicing (ie, within +/- 2 bp of an exon/intron junction), two publications found the variant to not affect splicing via functional studies (Caux-Moncoutier_2009, Houdayer_2012). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (4x). 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	RCV000077401	SCV000744518	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000077401	SCV001139180	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284108	SCV001469714	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing
Invitae	RCV001410830	SCV001612882	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-16	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077401	SCV000109198	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-11-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077401	SCV000147095	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	RCV001284108	SCV001550347	likely benign	not provided		no assertion criteria provided	clinical testing	BRCA2, EXON15, c.7463G>A, p.Arg2488Lys, Heterozygous, Likely BenignrnThe BRCA2 p.Arg2488Lys variant was identified in 3 of 7698 proband chromosomes (frequency: 0.0004) from individuals or families with breast or ovarian cancer (Claes 2004, Caux-Moncoutier 2009). The variant was also identified in dbSNP (ID: rs80358968) as "With other allele", ClinVar (classified as likely benign by GeneDx, Ambry Genetics, SCRP, Color and Integrated Genetics/Laboratory Corporation of America; and as uncertain significance by four submitters), LOVD 3.0 (14x), and UMD-LSDB (1x as neutral). In the UMD-LSDB database, the variant was identified in multiple cases as co-occurring with pathogenic BRCA1 variants (c.1961dup, p.Tyr655ValfsX18; c.4183C>T, p.Gln1395X; c.IVS21+1G>T, r.spl?; c.4389C>A, p.Tyr1463X; and c.442_4357del, p.Glu149TyrfsX2) and a pathogenic BRCA2 variant (c.2745_2746delTT, p.Val917LysfsX18), increasing the likelihood that the p.Arg2488Lys variant does not have clinical significance. The variant was identified in control databases in 3 of 246180 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33578 chromosomes (freq: 0.00003), European in 2 of 111652 chromosomes (freq: 0.00002), but not in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg2488 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The literature suggests a neutral classification of the variant. Caux-Moncoutier (2009) used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. In addition, Claes (2004) found that the variant did not segregate with disease in one family. In addition, several in silico and in vitro studies using PAXgene, Minigene systems or functional evidence identified no change and classified the variant neutral with no effect on splicing (Houdayer 2012, Martelotto 2014). 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.rnAssessment Date: 2019/07/22rnReferences (PMIDs): 15026808, 19471317, 22505045, 25348012, 19043619
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001284108	SCV001906359	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001284108	SCV001954475	uncertain significance	not provided		no assertion criteria provided	clinical testing