Submissions for variant NM_000059.4(BRCA2):c.2919G>A (p.Ser973=)

gnomAD frequency: 0.00012  dbSNP: rs45525041

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113113	SCV000578022	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0018 (South Asian), derived from ExAC (2014-12-17).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044085	SCV000072098	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000168560	SCV000167349	benign	not specified	2014-02-06	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	RCV000162604	SCV000213028	likely benign	Hereditary cancer-predisposing syndrome	2014-08-28	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768592	SCV000219320	likely benign	Breast and/or ovarian cancer	2020-06-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000113113	SCV000220910	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-24	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000113113	SCV000383663	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-28	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	RCV000308141	SCV000383664	likely benign	Fanconi anemia complementation group D1	2017-04-28	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.
Baylor Genetics	RCV000474196	SCV000541042	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000168560	SCV000586937	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162604	SCV000683511	likely benign	Hereditary cancer-predisposing syndrome	2015-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586047	SCV000694647	benign	not provided	2016-10-18	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2919G>A (p.Ser973Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 54/120514 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0017597 (29/16480). This frequency is about 2.35 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. This variant is known to co-occur with multupe deleterious variants in literature (Lara_Biol Res_2012) and in UMD (BRCA1 c.5123C>A (p.Ala1708Glu), c.5266dup (p.Gln1756ProfsX74), c.2722G>T (p.Glu908X), and c.3485delA (p.Asp1162ValfsX48) and BRCA2 c.1184G>A (p.Trp395X)), strongly supporting for a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign/likely beign. Taken together, this variant is classified as Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000586047	SCV001148977	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000168560	SCV001160046	benign	not specified	2018-10-16	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044085	SCV002026084	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168560	SCV002071272	likely benign	not specified	2022-01-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162604	SCV002533743	benign	Hereditary cancer-predisposing syndrome	2021-02-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168560	SCV002550314	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044085	SCV004228148	benign	Hereditary breast ovarian cancer syndrome	2023-10-10	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113113	SCV000146139	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-01-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358171	SCV001553842	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser973= variant was identified in 4 of 3750 proband chromosomes (frequency: 0.001) from Spanish, Cypriot, Greek, Italian and American individuals or families with FCCX (familial crc type X), and breast/ovarian (sporadic and familial) cancers and was not identified in 100 chromosomes from healthy individuals (Garre 2015, Hadjisavvas 2004, Konstantopoulou 2007, Minucci 2015, Borg 2010). The variant was also identified in dbSNP (ID: rs45525041) “With other allele”, ClinVar (classified benign, reviewed by an expert panel (June 2017); submitters: benign by ENIGMA, Invitae, GeneDx and Baylor Miraca Genetics Laboratories; likely benign by Ambry Genetics, CHEO, Counsyl, Illumina; and uncertain significance by BIC), Clinvitae (6x), LOVD 3.0 (1x), UMD-LSDB (36x as 3-uv, co-occurring with BRCA1 pathogenic variants: c.5123C>A; p.Ala1708Glu, c.5266dup; p.Gln1756ProfsX74, c.2722G>T; p.Glu908X), and BIC Database (1x, clinical importance unknown, classification pending). The variant was not identified in COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 88 of 275074 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include Latino in 7 of 34050 chromosomes (freq. 0.0002), European Non-Finnish in 33 of 125900 chromosomes (freq. 0.0003), and South Asian in 48 of 30236 chromosomes (freq. 0.002); it was not seen in the East Asian, African, other, Ashkenazi Jewish, and European Finnish populations. The p.Ser973= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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)	RCV000586047	SCV001798667	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000586047	SCV001905925	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586047	SCV001956043	likely benign	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113113	SCV004243597	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing