Submissions for variant NM_000059.4(BRCA2):c.1040A>G (p.Gln347Arg)

gnomAD frequency: 0.00109  dbSNP: rs55800493

Total submissions: 21

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, susceptibility to, 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 ovarian cancer syndrome	2024-01-31	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	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.
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)
Eurofins Ntd Llc (ga)	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, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000589778	SCV000805645	likely benign	not provided	2017-05-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589778	SCV000883473	likely benign	not provided	2022-05-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589778	SCV000887744	benign	not provided	2023-05-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131469	SCV000902747	benign	Hereditary cancer-predisposing syndrome	2016-01-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000173638	SCV002065673	uncertain significance	not specified	2018-09-12	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001079609	SCV002515246	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131469	SCV002533202	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000173638	SCV002550271	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077248	SCV000109045	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-05-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077248	SCV000145810	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000077248	SCV000745675	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-21	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000173638	SCV001905797	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000173638	SCV001978080	benign	not specified		no assertion criteria provided	clinical testing