ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2919G>A (p.Ser973=) (rs45525041)

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Total submissions: 19
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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 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).
Invitae RCV000044085 SCV000072098 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 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: 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 2015-12-11 criteria provided, single submitter clinical testing
Counsyl RCV000113113 SCV000220910 likely benign Breast-ovarian cancer, familial 2 2014-11-24 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000113113 SCV000383663 likely benign Breast-ovarian cancer, familial 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 Clinical Services Laboratory,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 Health, Inc 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 Praxis fuer Humangenetik Tuebingen RCV000586047 SCV001148977 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000168560 SCV001160046 benign not specified 2018-10-16 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113113 SCV000146139 uncertain significance Breast-ovarian cancer, familial 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
Human Genetics - Radboudumc,Radboudumc RCV000586047 SCV001956043 likely benign not provided no assertion criteria provided clinical testing

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