Submissions for variant NM_000059.4(BRCA2):c.10154G>A (p.Arg3385His)

gnomAD frequency: 0.00002  dbSNP: rs80358398

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086927	SCV000071735	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162743	SCV000213215	benign	Hereditary cancer-predisposing syndrome	2015-06-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768613	SCV000324844	likely benign	Breast and/or ovarian cancer	2015-09-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725588	SCV000337948	uncertain significance	not provided	2015-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000725588	SCV000512405	likely benign	not provided	2019-11-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22752604, 20960228)
Color Diagnostics, LLC DBA Color Health	RCV000162743	SCV000910750	benign	Hereditary cancer-predisposing syndrome	2016-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000374528	SCV000916866	likely benign	not specified	2023-09-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.10154G>A (p.Arg3385His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10154G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and other cancer phenotypes (examples- Kote-Jarai _2011, Laitman _2011, Juwle_2012, Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.7558C>T, p.Arg2520X; UMD database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Ikegami_2020). Tumors with pathogenic variants within BRCA and defective HDR have been shown to be particularly sensitive to platinum-based chemotherapies and poly (ADP-ribose) polymerase (PARP) inhibitors, the efficacy of which is mediated through synthetic lethality in cancer cells with BRCA loss-of function. These results showed no damaging effect of this variant on homology directed repair (HDR capacity) based on a high throughput cell based viability assay (MANO-B method) to evaluate drug sensitivity of the BRCA2 variants treated with PARP inhibitors (olaparib, niraparib, rucaparib and carboplatin) at various concentrations. The following publications have been ascertained in the context of this evaluation (PMID: 21952622, 22752604, 20960228, 24504028, 26689913, 32444794). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=6) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000725588	SCV001470189	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with breast cancer (PMID:22752604 (2012)) and prostate cancer (PMID:21952622 (2011)). A functional study showed inconclusive results regarding the variant's impact on protein function (PMID: 32444794 (2020)). The frequency of this variant in the general population, 0.000026 (3/113534 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001086927	SCV002025889	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031303	SCV004846275	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000374528	SCV005090083	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031303	SCV000053908	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031303	SCV000145761	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353958	SCV000592314	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Arg3385His variant was identified in 2 of 2626 proband chromosomes (frequency: 0.0008) from individuals or families with breast and ovarian cancer (Laitman 2011, Cunningham 2014). The variant was also identified in ClinVar (as benign by Ambry Genetics and SCRP, as likely benign by CHEO and GeneDx, as uncertain significance by Emory Genetics, Invitae and BIC), Genesight-COGR (as likely benign by CHEO), LOVD 3.0 (1x, function effect unknown, and unclassified), UMD (1x as VUS), BIC (3x, classification pending) databases. The variant was not identified in Cosmic, MutDB, ARUP Laboratories and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 4 of 245946 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg3385 residue is not conserved in mammals and the variant amino acid histamine (His) is present in dog, increasing the likelihood that this variant does not have clinical significance. In addition 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
True Health Diagnostics	RCV000162743	SCV000787915	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532431	SCV004709481	uncertain significance	BRCA2-related disorder	2023-11-20	no assertion criteria provided	clinical testing	The BRCA2 c.10154G>A variant is predicted to result in the amino acid substitution p.Arg3385His. This variant was reported in individuals with breast, ovarian, or prostate cancer (Laitman et al. 2011. PubMed ID: 20960228; Table S1, Kote-Jarai et al. 2011. PubMed ID: 21952622; Juwle et al. 2012. PubMed ID: 22752604; Table S1, Cunningham et al. 2014. PubMed ID: 24504028). Functional studies using PARP inhibitors showed that this variant does not significantly alter protein functions (Figure 2, Ikegami et al. 2020. PubMed ID: 32444794). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32972804-G-A) and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/37722). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.