ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8092G>A (p.Ala2698Thr) (rs80359052)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000074554 SCV000108639 likely benign not specified 2017-11-03 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 RCV000129982 SCV000184806 likely benign Hereditary cancer-predisposing syndrome 2018-04-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl RCV000031720 SCV000487854 uncertain significance Breast-ovarian cancer, familial 2 2015-11-23 criteria provided, single submitter clinical testing
Invitae RCV000531554 SCV000635637 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Mendelics RCV000531554 SCV000838867 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755863 SCV000883489 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing The BRCA2 c.8092G>A;p.Ala2698Thr variant has been described in the medical literature in an individual with breast cancer and a family history of cancer (Manguoglu 2010). The variant is listed in the ClinVar database (Variation ID: 38138), the dbSNP variant database (rs80359052), and the Genome Aggregation Database with an allele frequency of 0.004331 percent (12/277058 alleles). The amino acid at this position is weakly conserved across species, with several mammalian species with threonine at this position, and computational algorithms (AlignGVGD, SIFT, MutationTaster) predict this variant is tolerated. Considering available information, the clinical significance cannot be determined with certainty. References: Manguoglu E et al. Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients. Cancer Genet Cytogenet. 2010 Dec;203(2):230-7.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755863 SCV000889152 uncertain significance not provided 2020-01-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129982 SCV000905495 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074554 SCV000918820 likely benign not specified 2020-08-17 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8092G>A (p.Ala2698Thr) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251318 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8092G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as other cancer types (example, Dong_2018, Kandoth_2013, Lu_2015, Manguoglu_2010, Pal_2015, Wagner_1999, Lee_2018). At-least one of these publications reported re-classification of this variant from a VUS to likely benign supported by ACMG guidelines and a validated multifactorial probability model (Lee_2018). Therefore, these report(s) 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 observed at our laboratory (BRCA2 c.1321_1324delACTT, p.Thr441GlnfsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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=5, likely benign, n=4). Based on the evidence outlined above, the variant was re-classified as likely benign.
Mendelics RCV000031720 SCV001139205 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031720 SCV000054327 uncertain significance Breast-ovarian cancer, familial 2 2007-03-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031720 SCV000147272 uncertain significance Breast-ovarian cancer, familial 2 1998-11-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354237 SCV001548799 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ala2698Thr variant was identified in in 4 of 5634 proband chromosomes (frequency: 0.0007) from individuals or families with breast or ovarian cancer and was present in 1 of 290 control chromosomes (frequency: 0.003) from healthy individuals (Lee 2018, Manguoğlu 2010, Pal 2015, Wagner 1999, Encinas 2018). The variant was also identified in dbSNP (ID: rs80359052) as "with Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Sharing Clinical Reports Project (SCRP) and six other submitters; and as likely benign by Ambry Genetics, GeneDx and one other submitter), and the LOVD 3.0 database. The variant was not identified in the UMD-LSDB database. It was identified in control databases in 12 of 277058 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 24034 chromosomes (freq: 0.0003), Other in 1 of 6460 chromosomes (freq: 0.0002), and East Asian in 5 of 18860 chromosomes (freq: 0.0003), while the variant was not observed in the Latino, European, Ashkenazi Jewish, Finnish or South Asian populations. The p.Ala2698 residue is not conserved in mammals and 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) 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.

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