Submissions for variant NM_000059.4(BRCA2):c.4584C>T (p.Ser1528=)

gnomAD frequency: 0.00026  dbSNP: rs80359788

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113323	SCV000579175	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044445	SCV000072458	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000123973	SCV000167366	benign	not specified	2013-12-20	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	RCV000163135	SCV000213649	likely benign	Hereditary cancer-predisposing syndrome	2014-08-14	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	RCV000113323	SCV000220354	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-05-27	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000679173	SCV000225160	uncertain significance	not provided	2015-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113323	SCV000383700	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000305604	SCV000383701	likely benign	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044445	SCV000494386	benign	Hereditary breast ovarian cancer syndrome	2015-12-14	criteria provided, single submitter	clinical testing	Variant summary: The c.4584C>T variant, a synonymous mutation, lies in the middle of exon 11. This variant involves a non-conserved nucleotide and 5/5 in silico splice-site prediction tools via Alamut predict that the variant does not affect normal splicing. This prediction is consistent with the report from Caux-Moncoutier et al (Caux-Moncoutier et al 2009) in which the authors 'indirectly' show that the variant of interest does not result in allelic imbalance due to nonsense mediated decay of aberrant splice products. The variant was found in the general population at a frequency of 0.02% which does not exceed the maximal expected allele frequency of a pathogenic BRCA2 variant (which is 0.075%). However, the frequency of this variant in the Latino population is just above that of the maximal expected allele frequency (0.78%), which suggests this variant to be a polymorphism found mainly in populations of Latin descent. Indeed, several of the reported HBOC patients/families with the variant were from Spain, and co-occurrence and co-segregation were not reported for these patients, suggesting the true disease-causing mutation was not detected/presented. Furthermore, UMD reports co-occurrence with a possibly deleterious truncating BRCA2 variants c.6079dup (p.Arg2027LysfsX22) and c.4926_4935del (p.Asn1642LysfsX25) and with BRCA1 variant c.3331_3334delCAAG (p.Gln1111AsnfsX5) implicating that the variant of interest is in the benign spectrum. Additionally, publications (Osorio_BRCA2_Clin Genet_1998; Diez_BRCA2_HM_2003) and several clinical diagnostic laboratoris classify variant as Polymorphism/Bening/Likely Bening (without evidence to independently evaluate). Considering all evidence, the variant is classified as benign.
Baylor Genetics	RCV000471202	SCV000541070	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163135	SCV000683633	likely benign	Hereditary cancer-predisposing syndrome	2015-04-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113323	SCV000743300	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113323	SCV000744458	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679173	SCV000805708	likely benign	not provided	2017-06-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679173	SCV000883519	likely benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769693	SCV000901108	likely benign	Breast and/or ovarian cancer	2022-11-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000113323	SCV001139092	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679173	SCV001148985	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
Genetic Services Laboratory, University of Chicago	RCV000123973	SCV002068231	likely benign	not specified	2019-06-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163135	SCV002533883	likely benign	Hereditary cancer-predisposing syndrome	2020-11-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123973	SCV004027428	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044445	SCV004228080	benign	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000679173	SCV005215524	likely benign	not provided		criteria provided, single submitter	not provided
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113323	SCV000146452	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353832	SCV000591911	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser1528Ser variant was identified in 25 of 1248 proband chromosomes (frequency: 0.04) from Spanish families with breast and ovarian cancer, and was not identified in 200 control chromosomes from healthy individuals (Diez 2003).The variant was also identified in dbSNP (ID: rs80359788) “With Uncertain significance allele”, with a minor allele frequency of 0.001 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), LOVD, the ClinVar database (with one “uncertain significance” classification from BIC, benign submission from Invitae and benign submission from GeneDX), the BIC database (2X with unknown clinical importance), and UMD (21X as a neutral variant). In addition, Myriad classifies this as a polymorphism (personal communication). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.3331_3334delCAAG (p.Gln1111AsnfsX5) of BRCA1gene and c.4926_4935del (p.Asn1642LysfsX25) of BRCA2 gene), increasing the likelihood that the p.Ser1528Ser variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 2 of 2000 chromosomes (frequency: 0.001), Exome Variant Server project in 3 of 4406 African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Ser1528Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.The p.Ser1528Ser variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs(SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000113323	SCV000745677	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-21	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000163135	SCV000805243	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679173	SCV001952133	likely benign	not provided		no assertion criteria provided	clinical testing