ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5768A>C (p.Asp1923Ala) (rs45491005)

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Total submissions: 15
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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) RCV000031576 SCV001161665 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00310 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV000195306 SCV000072761 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131532 SCV000186526 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: 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.
GeneDx RCV001537845 SCV000210371 likely benign not provided 2021-01-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10800284, 23555315, 21520273, 18284688, 25348012, 25801821, 23704879, 22034289, 20104584)
Michigan Medical Genetics Laboratories,University of Michigan RCV000031576 SCV000267786 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195306 SCV000494400 likely benign Hereditary breast and ovarian cancer syndrome 2016-05-16 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5768A>C (p.Asp1923Ala) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 34/121054 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0032372 (33/10194). This frequency is about 4 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 African origin. One co-occurrence with BRCA1 c.2679_2682delGAAA was found in one individual (BRCA Share database). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000044748 SCV000885096 likely benign not specified 2019-03-15 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770727 SCV000902207 likely benign Breast and/or ovarian cancer 2017-08-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131532 SCV000910703 benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642391 SCV001854857 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031576 SCV000054182 benign Breast-ovarian cancer, familial 2 2009-02-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031576 SCV000146692 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353544 SCV000592000 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asp1923Ala variant was identified in 12 of 5074 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Borg 2010, Fackenthal 2012). The variant was also identified in dbSNP (ID: rs45491005) as “With Uncertain significance, other allele”, the ClinVar database (classified as benign by Invitae, Ambry Genetics, SCRP; likely benign by GeneDx, MMGLUM; uncertain significance by BIC), COGR database (classified as uncertain significance by one clinical laboratory), the BIC database (9x with unknown importance) and UMD (29x with a “likely neutral” classification). In UMD the variant was identified with a co-occurring pathogenic BRCA1 (c.2679_2682delGAAA, p.Lys893AsnfsX106) and BRCA2 variants (c.7558C>T, p.Arg2520X), increasing the likelihood that the p.Asp1923Ala variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the NHLBI GO Exome Sequencing Project in 13 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) and the Genome Aggregation Database (October 3, 2017) in 78 of 276432 chromosomes (freq. 0.0003). The variant was observed in the following populations: in 75 of 24020 African chromosomes (freq. 0.0003), “Other” in 2 of 6450 chromosomes (freq. 0.0003), and Latino in 1 of 34326 chromosomes (freq. 0.00001), but was not seen in Asian, European, or Finnish populations. The p.Asp1923 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. One study predicted the variant to abolish kinase binding; however this was only based on in silico results (Tram 2013). 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.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV001537845 SCV001905786 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001537845 SCV001931090 likely benign not provided no assertion criteria provided clinical testing

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