ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9175A>G (p.Lys3059Glu) (rs80359174)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000114059 SCV001161628 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000879
Invitae RCV001079907 SCV000073750 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130061 SCV000184888 likely benign Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000766656 SCV000278886 likely benign not provided 2020-06-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19043619, 31131967)
Counsyl RCV000114059 SCV000488180 uncertain significance Breast-ovarian cancer, familial 2 2016-01-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130061 SCV000903036 likely benign Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000217640 SCV000918983 uncertain significance not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9175A>G (p.Lys3059Glu) results in a conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246114 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9175A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.8237_8238delCA/p.Thr2746Serfs; BRCA2 c.8575delC/p.Q2859fsX4), providing supporting evidence for a benign role. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Research and Development, ARUP Laboratories RCV001646902 SCV001852832 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA2) RCV000114059 SCV000147558 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000114059 SCV000297577 likely benign Breast-ovarian cancer, familial 2 2011-07-05 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353881 SCV000592262 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Lys3059Glu variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80359174) as “With other allele”; in ClinVar and Clinvitae as likely benign by Invitae, Ambry Genetics, Sharing Clinical Reports Project, and with uncertain significance by GeneDx and Counsyl. In addition, the variant was listed in the BIC database 3X with unknown significance; in LOVD 3.0 database 1X with no classification; in the UMD-LSDB database 2X as uncertain significance with no co-occurrence of other pathogenic variants; and in the BIC Database 3X with unknown significance. The variant was also identified by our laboratory in 2 individuals with breast cancer. Furthermore, the variant was identified in control databases in 1 of 246114 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was identified in the European Non-Finnish population in 1 of 111604 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In silico predicted impact on the protein is uncertain (Karchin_2008). The p.Lys3059 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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. This variant is classified as a variant of uncertain significance.

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