ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7522G>A (p.Gly2508Ser) (rs80358978)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084266 SCV000073249 benign Hereditary breast and ovarian cancer syndrome 2020-10-26 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 2019-12-13 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 numerous Asian breast and ovarian cancer cohorts (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; Yoon KA et al. Cancer Res Treat. 2017 Jul;49:627-634; Ng PS et al. Clin. Genet. 2016 Oct;90:315-23; Liang Y et al. Med. Sci. Monit. 2018 Apr;24:2465-2475; Li JY et al. Int. J. Cancer. 2019 Jan;144:281-289). Although this alteration has also been detected in a cohort of healthy individuals (Bodian DL et al. PLoS One. 2014 Apr;9:e94554), 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). This alteration has also been detected in 5/2575 unselected patients with breast cancer and 5/2809 healthy control individuals from a Malaysian cohort (Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103). 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). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, 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 2020-09-04 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). Ten 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 (5x), likely benign (3x), or benign (2x)). 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 Health, Inc 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 2020-01-21 criteria provided, single submitter clinical testing
Mendelics RCV000077404 SCV001139184 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000203651 SCV001502170 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing
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 2 2008-10-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077404 SCV000147112 uncertain significance Breast-ovarian cancer, familial 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.