Submissions for variant NM_000059.4(BRCA2):c.9104A>C (p.Tyr3035Ser)

dbSNP: rs80359165

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045717	SCV000073730	benign	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130861	SCV000185760	likely benign	Hereditary cancer-predisposing syndrome	2018-12-07	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	RCV000589726	SCV000210679	likely benign	not provided	2021-02-01	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27221827, 10923033, 24728327, 25782689, 25971625, 20104584, 18627636, 19043619, 23231788, 26183948, 27616075, 28324225, 28283652, 21952622, 22711857, 21673748, 22476429, 29394989, 29088781, 24094589, 20167696, 29341116, 29988080, 30254663, 28726806, 29684080, 31409081, 31300551, 31294896, 32444794, 31131967, 31954625, 32123317, 29884841)
Color Diagnostics, LLC DBA Color Health	RCV000130861	SCV000684025	likely benign	Hereditary cancer-predisposing syndrome	2015-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120368	SCV000695213	benign	not specified	2022-10-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9104A>C (p.Tyr3035Ser) results in a non-conservative amino acid change located in the DNA-binding domain (Shimelis 2017, Guidugli 2018) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 345886 control chromosomes (gnomAD and publication data), predominantly found within the Non-Finnish European subpopulation at a frequency of 9.8e-05. This frequency is not higher than the estimated maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (HBOC) Syndrome (0.00075), allowing no conclusion about variant significance. The variant, c.9104A>C, has been reported in the literature in several individuals affected with prostate cancer, breast cancer and ovarian cancer (e.g. Kote-Jarai 2011, Moghadasi 2013, Alsop 2012, Muendlein 2015, Dodova 2015, Shimelis 2017, Sadowski 2017, Alvarez 2017, Jakimovska 2018, Zuntini 2018, Fostira_2020), however it also was found in several healthy controls (e.g. Dodova 2015, Shimelis 2017). In addition, multiple co-occurrences with other pathogenic variants have been reported (BRCA1 c.2603C>G (p.Ser868X), BRCA2 c.1540_1549del (p.Glu514MetfsX8) and BRCA2 c.7913_7917delTTCCT (p.Phe2638X) in the UMD database; and BRCA2 c.5645C>A (p.Ser1882X) in Shimelis 2017), providing supporting evidence for a benign role. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated no effect on splicing (Thery_2011, Wai_2020), and a mild impact on BRCA2 protein function, representing an activity comparable to wild-type, or a somewhat hypomorphic allele (e.g. Shimelis 2017, Guidugli 2018, Mesman 2018, Ikegami_2020). One case-control study found that this variant was associated with moderately increased risks of breast cancer for Caucasian women (odds ratio (OR) = 2.52; P = 0.04), and while the number of cases and controls with the Y3035S variant were relatively small, this moderate risk estimate was supported by family pedigree analysis, showing partial co-segregation with breast cancer (Shimelis 2017). On the other hand, in a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 12/60466 cases, and in 7/53461 controls (Dorling 2021 through LOVD), indicating a much lower odds ratio that is well below the OR of BRCA2 truncations (5.85 [95% CI: 4.85-7.06]) or pathogenic BRCA2 missense variants (5.68 [95% CI: 2.62 to 12.29]) reported in this study (Dorling 2021). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be (likely) neutral (Parsons 2019, Caputo 2021). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (benign, n=1; likely benign, n=4; VUS, n=4). Based on the evidence outlined above, the variant of interest represents a neutral- or mildly hypomorphic variant, however, it is not a high penetrance causative variant within the settings of inherited Hereditary Breast and Ovarian Cancer Syndrome. Therefore, the variant was classified as benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031794	SCV000744554	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735620	SCV002043668	uncertain significance	Breast and/or ovarian cancer	2020-01-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589726	SCV002046896	likely benign	not provided	2023-04-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130861	SCV002532007	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589726	SCV004563113	likely benign	not provided	2023-04-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589726	SCV004700619	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP2, BS3:Supporting
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000031794	SCV005043266	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-08	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120368	SCV005090072	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031794	SCV000054402	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-08-18	no assertion criteria provided	clinical testing
ITMI	RCV000120368	SCV000084520	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031794	SCV000147538	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000045717	SCV000586990	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353989	SCV000592258	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr3035Ser variant was identified in 28 of 105,838 proband chromosomes (frequency: 0.0003) from individuals or families with prostate and hereditary breast and ovarian cancer and was present in 8 of 98,938 control chromosomes (frequency: 0.00008) from healthy individuals (Moghadasi 2013, Kote-Jarai 2011, Alsop 2012, Dodova 2015, Muendlein 2015, Kraus 2017, Meisel 2017, Shimelis 2017). The variant was identified in dbSNP (rs80359165) as “with uncertain significance, other allele”, ClinVar (classified as uncertain significance by GeneDx, Integrated Genetics BIC, Sinai Health System and 4 other submitters, likely benign by Ambry Genetics, Color and Invitae and benign by SCRP), LOVD 3.0 (observed 27x) and UMD-LSDB (observed 19x). The variant was identified in control databases in 14 of 280,642 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 13 of 127,670 chromosomes (freq: 0.0001), Latino in 1 of 35,294 chromosomes (freq: 0.00003), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The variant co-segregated with disease in multiple high-risk breast cancer families (Shimelis 2017). In UMD-LSDB, the variant was observed in samples with co-occurring pathogenic BRCA2 (c.1540_1549del p.Glu514Metfs*8, c.7913_7917delTTCCT p.Phe2638*) and BRCA1 (c.2603C>G p.Ser868*) variants. In one study, in vitro expression of the variant altered homology directed repair activity and decreased BRCA2 DNA binding (Shimelis 2017). The p.Tyr3035 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 a variant of uncertain significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735620	SCV000863758	uncertain significance	Breast and/or ovarian cancer	2013-10-11	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000031794	SCV004228459	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP4(Supporting)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
PreventionGenetics, part of Exact Sciences	RCV004732581	SCV005350416	uncertain significance	BRCA2-related disorder	2024-07-16	no assertion criteria provided	clinical testing	The BRCA2 c.9104A>C variant is predicted to result in the amino acid substitution p.Tyr3035Ser. This variant has been reported in a prostate cancer cohort (Kote-Jarai et al. 2011. PubMed ID: 21952622, Table S1) and in several hereditary breast cancer studies (Muendlein et al. 2015. PubMed ID: 25971625, Tables 1 and 3; Meisel et al. 2017. PubMed ID: 28324225, Table 4; Shimelis et al. 2017. PubMed ID: 28283652), all of which interpreted this variant as uncertain significance. This variant was also reported in the heterozygous state as probably damaging in one individual with lipid metabolism deficiency (Supplementary Table S3. Dong et al. 2022. PubMed ID: 35460704). However, this variant has been reported in a healthy, ancestrally diverse cohort (Bodian et al. 2014. PubMed ID: 24728327, Table S1). The results of in silico models and in vitro functional assays from several studies are conflicting, citing the pathogenicity of this variant as likely benign, uncertain, and likely pathogenic (Karchin et al. 2008. PubMed ID: 19043619, Table S1; Mesman et al. 2018. PubMed ID: 29988080, Table 2; Cline et al. 2019. PubMed ID: 31294896; Ikegami et al. 2020. PubMed ID: 32444794; Wai et al. 2020. PubMed ID: 32123317; Hu et al. 2022. PubMed ID: 35736817). This variant has been reported at a frequency of ~0.01% in individuals of European (Non-Finnish) origin in a large population database and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/38211/).  An internal summary of amino acid substitution prediction programs predicts the p.Tyr3035Ser change to be “conflicting” (Liu et al. 2016. PMID: 26555599). Based on these observations, the c.9104A>C variant is classified as uncertain.