ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3218A>G (p.Gln1073Arg) (rs80358566)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083043 SCV000072163 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-28 criteria provided, single submitter clinical testing
GeneDx RCV000074524 SCV000108609 likely benign not specified 2018-01-23 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 RCV000129622 SCV000184415 likely benign Hereditary cancer-predisposing syndrome 2018-11-14 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Counsyl RCV000031409 SCV000488158 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588491 SCV000694677 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3218A>G (p.Gln1073Arg) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict benign outcome for this variant. This variant was found in 6/119496 control chromosomes from ExAC at a frequency of 0.0000502, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been found in multiple patients with breast and/or ovarian cancer, prostate cancer, urothelial cancer and uterine cancer (Alsop_2012, Lu_2012, Maier_2014, Rodriguez-Vida_2014. Lu_2015); however, no strong evidence for or against pathogenicity is present. Functional studies show that this variant alters the BRCA2-APRIN interaction independently of the BRC1-RAD51 interaction and homologous recombination (Brough_2012). Clinical diagnostic laboratories/reputable databases have classified this variant as likely benign (3) as well as uncertain significance (4). Taken together, this variant is classified as Variant of Unknown Significance.
Color Health, Inc RCV000129622 SCV000902935 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588491 SCV001470410 uncertain significance not provided 2020-08-18 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031409 SCV000054014 likely benign Breast-ovarian cancer, familial 2 2013-03-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031409 SCV000146193 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 RCV001357102 SCV001552453 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Gln1073Arg variant was identified in dbSNP (ID: rs80358566) as “other”, Clinvitae database (classified as likely benign by ClinVar; uncertain significance by ClinVar and Invitae), the ClinVar database (classified as likely benign by SCRP, GeneDx; uncertain significance by Invitae, Ambry Genetics, BIC), the BIC database (3x with unknown clinical importance). This variant was also identified in the Exome Aggregation Consortium database (August 8th 2016) in 6 of 119496 chromosomes (freq. 0.00005) in the European population in 6 of 65970 chromosomes (freq.0.0001), but was not seen in African, Asian, Finnish, Latino and Other populations. The variant was not identified in the Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database, COSMIC and GeneInsight-COGR databases. The p.Gln1073 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a cryptic 3’ splice site. However, this information is not predictive enough to assume pathogenicity. In addition, the variant was identified, in a sample used as a positive control, as co-occurring with a pathogenic variant in BRCA1 (c.5136G>A, p.Trp1712X), increasing the likelihood this variant does not have clinical significance (Mucaki 2016). 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.

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