ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1040A>G (p.Gln347Arg) (rs55800493)

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Total submissions: 17
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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) RCV000077248 SCV001161577 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 0.00415 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV001079609 SCV000071747 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131469 SCV000186456 likely benign Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000589778 SCV000210554 likely benign not provided 2021-05-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25348012, 20104584, 26315209, 24504028, 23555315, 18284688, 21520273)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173638 SCV000224769 likely benign not specified 2015-01-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589778 SCV000694503 likely benign not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.1040A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Arg. 4/5 in-silico tools predict this variant to be benign. This variant is found in 47/120376 control chromosomes at a frequency of 0.0003904, however is present at 10-fold higher frequency in the African population (0.004533 in ExAC), which exceeds the maximum expected allele frequency for a pathogenic variant in BRCA2 (0.0007503). This suggests that this variant is a benign polymorphism in populations of African origin. This variant has been reported in BrC or OvC patients without evidence for causality. Multiple clinical laboratories classified this variant as benign/likely benign. Taken together, this variant is classified as Likely Benign until additional information becomes available.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077248 SCV000744400 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000077248 SCV000745675 likely benign Breast-ovarian cancer, familial 2 2017-05-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000589778 SCV000805645 likely benign not provided 2017-05-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283019 SCV000883473 likely benign none provided 2020-08-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589778 SCV000887744 benign not provided 2019-03-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131469 SCV000902747 benign Hereditary cancer-predisposing syndrome 2016-01-05 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642578 SCV001854661 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) RCV000077248 SCV000109045 likely benign Breast-ovarian cancer, familial 2 2008-05-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077248 SCV000145810 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 RCV001353763 SCV000591726 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Gln347Arg variant was identified in dbSNP (ID: rs55800493) “With likely benign, other allele”, with a minor allele frequency of 0.0024 (1000 Genomes Project), Clinvitae database, the ClinVar database (classified as a “likely benign” by Invitae, Ambry Genetics, GeneDx, Emory Genetics Laboratory and Sharing Clinical Reports Project), the BIC database (9X with unknown clinical importance), and UMD (2X as an unknown variant). This variant was also identified in the Exome Variant Server project in 17 of 4400 European American alleles, and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 45 of 9928 chromosomes (frequency: 0.0045) from a population of African individuals. The variant was also found at low frequencies in Latino (8.66E-05) and European (Non-Finnish) individuals (1.51E-05), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Gln347 residue is not conserved in mammals and 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. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000173638 SCV001905797 benign not specified no assertion criteria provided clinical testing

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