ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10089A>G (p.Ile3363Met) (rs80358390)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043709 SCV000071722 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131377 SCV000186353 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing The p.I3363M variant (also known as c.10089A>G), located in coding exon 26 of the BRCA2 gene, results from an A to G substitution at nucleotide position 10089. The isoleucine at codon 3363 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in 2/206 Indian breast and/or ovarian cancer patients (Mehta A et al. Cancer Manag Res, 2018 Nov;10:6505-6516) and in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000425048 SCV000516584 likely benign not specified 2017-06-15 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588809 SCV000600452 uncertain significance not provided 2020-07-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588809 SCV000694491 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.10089A>G (p.Ile3363Met) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 11/121126 control chromosomes at a frequency of 0.0000908, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in one patient with epithelial cancer in a published study without strong evidence for pathogenicity (Cunningham_2014). It has also been reported in individuals undergoing BRCA1/2 testing by clinical testing labs and databases. Multiple clinical labs/databases have classified this variant as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
GeneKor MSA RCV000131377 SCV000821930 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131377 SCV000910907 likely benign Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112836 SCV000145748 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Centre for Molecular Diagnostics & Cell Biology,Rajiv Gandhi Cancer Institute & Research Center RCV000112836 SCV000485083 uncertain significance Breast-ovarian cancer, familial 2 2016-12-28 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353943 SCV000592310 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ile3363Met variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs80358390) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity; classified likely benign by Invitae, GeneDx and uncertain significance by Ambry Genetics, Quest Diagnostics Nichols Institute San Juan Capistrano, BIC and Centre for MolecularDiagnostics & Cell Biology (Rajiv Gandhi Caner Institute & Research Center)), Clinvitae (4x), UMD-LSDB (2x as 3-UV), BIC Database (1x with clinical importance unknown, classification pending), and in control databases in 24 of 276930 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24010 chromosomes (freq: 0.00004), European Non-Finnish in 2 of 126512 chromosomes (freq: 0.00002), and South Asian in 21 of 30772 chromosomes (freq: 0.0007). while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Ile3363 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood Met impacts 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, 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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