Submissions for variant NM_000059.4(BRCA2):c.7522G>A (p.Gly2508Ser)

gnomAD frequency: 0.00004  dbSNP: rs80358978

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084266	SCV000073249	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000120359	SCV000210654	likely benign	not specified	2017-12-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000164682	SCV000215349	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	The p.G2508S variant (also known as c.7522G>A), located in coding exon 14 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7522. The glycine at codon 2508 is replaced by serine, an amino acid with similar properties. This alteration has been detected in multiple individuals diagnosed with breast and/or ovarian cancer (Suter NM et al. Cancer Epidemiol. Biomarkers Prev. 2004 Feb;13:181-9; Lim MC et al. J. Cancer Res. Clin. Oncol. 2009 Nov;135:1593-9; Ng PS et al. Clin. Genet. 2016 Oct;90:315-23; Yoon KA et al. Cancer Res Treat. 2017 Jul;49:627-634; Liang Y et al. Med. Sci. Monit. 2018 Apr;24:2465-2475; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103; Li JY et al. Int. J. Cancer. 2019 Jan;144:281-289; Zhang Y et al. BMC Cancer, 2022 Aug;22:842). Multiple case-control studies and a meta-analysis of the participants from the Breast Cancer Association Consortium and the Shanghai Breast Cancer Genetic Study show a statistically increased association of this variant with breast cancer (Zhang Y et al. Cancer Epidemiol. Biomarkers Prev. 2014 Apr;23:622-8; Han MR et al. Carcinogenesis. 2017 May;38:511-518; Shimelis H et al. Cancer Res. 2017 Jun;77:2789-2799). Various functional assays indicate that this alteration is intermediately impaired with respect to rescue of lethality in Brca2-null mouse embryonic stem cells, homology directed repair in two cell lines, and PARP inhibition (Shimelis H et al. Cancer Res. 2017 Jun;77:2789-2799). This alteration has been seen with two different pathogenic mutations and one likely pathogenic variant in BRCA2 (phase unknown) in individuals whose clinical histories are not suggestive of Fanconi Anemia (Ambry internal data). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240741	SCV000265956	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000120359	SCV000602837	uncertain significance	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120359	SCV000695074	likely benign	not specified	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7522G>A (p.Gly2508Ser) results in a non-conservative amino acid change located in the helical domain (IPR015252) 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 0.0002 in 310330 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.7522G>A, has been reported in the literature in numerous individuals affected with tumors that belong to the HBOC spectrum, however it was also found in several healthy controls. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.8340_8343delTAAC (p.Asn2781ValfsX39) in the BIC database and BRCA1 c.3627dupA (p.Glu1210Argfs) in Lim_2009), providing supporting evidence for a benign role. A large case-control study involving breast cancer patients and controls of Asian ancestry (Han_2017), found an enrichment of this variant in cases (OR: 3.02 (95%CI: 1.69-5.39), p-value: 0.000123). However, an other case-control association study, involving breast cancer patients and controls of Japanese ancestry (Momozawa_2018), did not demonstrate significant increase in breast/ovarian cancer risk (i.e. the variant was identified in 5/7051 female cases, and 6/11241 female controls; OR: 1.3 (95%CI: 0.3-5.2)). A further study, involving Korean breast cancer patients, where multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology), predicted this variant to be likely pathogenic, although the variant was interpreted as likely benign when applying the ACMG/AMP guidelines (Lee_2018). Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated a mild impact on BRCA2 function, representing an activity comparable to wild-type, or a somewhat hypomorphic allele (e.g. Shimelis_2017, Mesman_2018, Guidugli_2018, Ikegami_2020). Eleven other 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 (VUS, n=6, likely benign, n=3 or benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
3DMed Clinical Laboratory Inc	RCV000677860	SCV000804021	uncertain significance	Infiltrating duct carcinoma of breast	2017-07-21	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677861	SCV000804022	uncertain significance	Ovarian cancer	2017-07-21	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677862	SCV000804023	uncertain significance	Cancer of the pancreas	2017-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164682	SCV000910752	likely benign	Hereditary cancer-predisposing syndrome	2016-11-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000203651	SCV001133904	likely benign	not provided	2023-08-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000077404	SCV001139184	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120359	SCV002067635	uncertain significance	not specified	2018-11-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164682	SCV002531868	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
ITMI	RCV000120359	SCV000084511	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077404	SCV000109201	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-10-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077404	SCV000147112	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	RCV001353972	SCV000592120	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2, p.Gly2508Ser variant was identified in 6 of 1220 proband chromosomes (frequency: 0.005) from individuals or families with breast, ovarian and thyroid cancers. (Lim 2009, Yu 2015, Wong 2016). The variant was also identified 1x in a study of 681 health controls in an east Asian individual (Bodian 2014). The variant was also identified in dbSNP (ID: rs80358978) “With other allele.” This variant was identified in the Exome Aggregation Consortium (ExAC) database (March 14, 2016) in 13 of 8636 chromosomes (frequency: 0 0.0015) in the East Asian population, and was not found in populations of South Asians, European (Non-Finnish), African, Latino, European (Finnish) and other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In the Clinvar Database the variant was identified with conflicting interpretations: as likely benign by Invitae, GeneDX and Sharing Reports Project derived from Myriad reports, as uncertain significance by Ambry Genetics and BIC,classification was not provided by ITMI. In BIC the variant was identified 4x with unknown clinical significance. In the Fanconi Anaemia Mutation Database (LOVD) the variant was identified 2x (1x as neutral by Karchin 2008 and 1x as deleterious by Pettigrew 2008). This variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), COSMIC, GeneInsight COGR, or ARUP Laboratories Databases. The p.Gly2508 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ser (Serine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Karchin et al 2008 has concluded the variant as predicted neutral using protein likelihood ratios to determine all variants of undetermined significance in the C-terminal binding domain of the BRCA2 protein. However, the variant was predicted to result in an increased exonic splice enhancer (ESE) motif score at an evolutionarily conserved ESE (Pettigrew 2008) and therefore the variant was concluded to be deleterious. In a multigene panel study of breast cancer predisposition in Asians, the authors categorized the p.Gly2508Ser variant as pathogenic using Manchester and Boadicea scores. Family history was evaluated in this multigene study (Wong 2016). 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250521	SCV002520832	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV000677861	SCV003843570	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing