Submissions for variant NM_000059.4(BRCA2):c.8215G>A (p.Val2739Ile)

gnomAD frequency: 0.00009  dbSNP: rs80359069

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080912	SCV000073466	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129733	SCV000184538	likely benign	Hereditary cancer-predisposing syndrome	2018-10-05	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.
GeneDx	RCV000045453	SCV000278879	likely benign	not provided	2021-09-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24094589, 26580448, 26689913, 25348012, 21702907, 19043619, 21218378, 25682074, 25556971)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000214196	SCV000494391	benign	not specified	2021-04-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8215G>A (p.Val2739Ile) results in a conservative amino acid change located in the OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249656 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8215G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for pathogenicity (Carney_2010, Trujillano_2015, Wong-Brown_2015, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the BIC database and observed at our laboratory (BRCA2 c.6486_6489delACAA , p.Lys2162fsX5 at our laboratory; BRCA1 c.81-2delA in BIC database), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair activity and in a mouse embryonic stem cell-based cell survival plus drug sensitivity assay (Karchin_2008, Biswas_2020). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=6; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045453	SCV000600791	likely benign	not provided	2020-02-18	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077431	SCV000744538	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000077431	SCV000785552	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129733	SCV000902886	likely benign	Hereditary cancer-predisposing syndrome	2015-07-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110061	SCV001267449	uncertain significance	Fanconi anemia complementation group D1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000077431	SCV001267450	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000077431	SCV001481482	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-04-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a patient with breast or ovarian cancer [PMID 25556971]
Sema4, Sema4	RCV000129733	SCV002531924	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149693	SCV003838179	likely benign	Breast and/or ovarian cancer	2022-05-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537208	SCV004117290	uncertain significance	BRCA2-related disorder	2023-05-23	criteria provided, single submitter	clinical testing	The BRCA2 c.8215G>A variant is predicted to result in the amino acid substitution p.Val2739Ile. This variant has been reported in an individuals with breast cancer and in individuals undergoing hereditary cancer testing (Table 3, Trujillano et al. 2015. PubMed ID: 25556971; Table 1, Carney et al. 2010. PubMed ID: 2128378; Supplement, Hondow et al. 2011. PubMed ID: 21702907; Supplement, Tung et al. 2015. PubMed ID: 25186627; Table S2, Wong-brown et al. 2015. PubMed ID: 25682074). Experimental evaluation using a homology-directed repair assay was inconclusive (Table S2, Karchin et al. 2008. PubMed ID: 19043619). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), and has conflicting interpretations of pathogenicity ranging from benign to uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/52529/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045453	SCV004563156	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The BRCA2 c.8215G>A; p.Val2739Ile variant (rs80359069) is reported in the literature in individuals affected with breast and/or ovarian cancer (Carney 2010, Trujillano 2015). This variant is reported as uncertain significance or likely benign by multiple laboratories in ClinVar (Variation ID: 52529), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268) Functional analyses of the variant protein show near WT levels of repair activity and mouse embryonic stem cell-based assay shows functional cell survival and drug sensitivity (Biswas 2020, Karchin 2008). Due to limited information, the clinical significance of the p.Val2739Ile variant is uncertain at this time. References: Biswas K et al. A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays. NPJ Genom Med. 2020 Dec 8;5(1):52. PMID: 33293522. Carney ME et al. Detection of BRCA1 and BRCA2 mutations in a selected Hawaii population. Hawaii Med J. 2010 Nov;69(11):268-71. PMID: 21218378. Karchin R et al. Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. Cancer Inform. 2008;6:203-16. PMID: 19043619. Trujillano D et al. Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer. J Mol Diagn. 2015 Mar;17(2):162-70. PMID: 25556971.
Sharing Clinical Reports Project (SCRP)	RCV000077431	SCV000109229	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077431	SCV000147300	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	RCV001353878	SCV000592179	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val2739Ile variant was identified in 10 of 3474 proband chromosomes (frequency: 0.003) from Australian, Polish, German and Hawaiian individuals or families with triple negative breast cancer or HBOC (Wong-Brown 2015 25682074, Lai 2015, Hondow 2011 21702907, Carney 2010 21218378, Trujillano 2015 25556971, Bosdet 2013 24094589). In a computational method that produces a probabilistic likelihood ratio predictive of impaired protein function, the variant was found to be neutral consistent with previously reported functional data related to homology directed repair (Karchin 2008). The variant was also identified in dbSNP (ID: rs80359069) “With Likely benign, Uncertain significance, other allele”, ClinVar (classified benign by Invitae, likely benign by Ambry Genetics, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano, and uncertain significance by Laboratory Corporation of America, SCRP and BIC), Clinvitae (5x), LOVD 3.0 (10x as predicted neutral and unknown function), UMD-LSDB (13x unclassified), BIC Database (6x unknown clinical importance, classification pending), and was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 244404 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017), in the East Asian population in 2 of 17246 chromosomes (freq: 0.0001), while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish and South Asian populations. The p.Val2739 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the p.Val2739Ile variant impacting 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000045453	SCV001905871	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000045453	SCV001958988	likely benign	not provided		no assertion criteria provided	clinical testing