Submissions for variant NM_000059.4(BRCA2):c.3218A>G (p.Gln1073Arg)

gnomAD frequency: 0.00009  dbSNP: rs80358566

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083043	SCV000072163	likely benign	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000588491	SCV000108609	likely benign	not provided	2019-05-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28726806, 27067391, 26497743, 22293751, 22711857, 25111659)
Ambry Genetics	RCV000129622	SCV000184415	likely benign	Hereditary cancer-predisposing syndrome	2018-11-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Counsyl	RCV000031409	SCV000488158	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003389627	SCV000694677	uncertain significance	not specified	2024-09-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3218A>G (p.Gln1073Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 242708 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.3218A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer, prostate cancer, urothelial cancer and uterine cancer (Zhu_2020, Alsop_2012, Lu_2012, Maier_2014, Rodriguez-Vida_2014, Lu_2015), without strong evidence for causality. In addition, this variant has been reported insignificantly present in both case and control cohorts in a large case-control study of breast cancer (4/60466 cases vs 3/53461 controls, Dorling_2021). Functional studies show that this variant alters the BRCA2-APRIN interaction independently of the BRC1-RAD51 interaction but was able to partially rescue homologous recombination in BRCA2-deficient cells to about 65% of normal function (Brough_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22711857, 22293751, 33471991, 22476429, 26689913, 25111659, 26497743, 31265121). ClinVar contains an entry for this variant (Variation ID: 37828). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	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	2021-05-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798041	SCV002042627	likely benign	Breast and/or ovarian cancer	2023-01-25	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129622	SCV003851774	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV001083043	SCV004228284	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-08	criteria provided, single submitter	curation	. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterium: BP1 (strong benign): BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (spliceAI: BRCA2: 0.0)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003389627	SCV005090026	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031409	SCV000054014	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-03-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031409	SCV000146193	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	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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000031409	SCV004099426	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732562	SCV005360363	uncertain significance	BRCA2-related disorder	2024-06-24	no assertion criteria provided	clinical testing	The BRCA2 c.3218A>G variant is predicted to result in the amino acid substitution p.Gln1073Arg. This variant has been reported in individuals and families affected with breast and/or ovarian cancer and prostate cancer (Alsop et al. 2012. PubMed ID: 22711857; Lu et al. 2012. PubMed ID: 22476429; Maier et al. 2014. PubMed ID: 25111659; Lu at al. 2015. PubMed ID: 26689913, Supplementary Data 12). A functional study showed that this variant alters the normal BRCA2 protein function (Brough et al. 2012. PubMed ID: 22293751). This variant occurs within a region of the BRCA2 gene that is predicted to be tolerant to missense variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/37828/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.