ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9986A>G (p.Asn3329Ser) (rs76635144)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130425 SCV000185289 likely benign Hereditary cancer-predisposing syndrome 2018-11-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000197376 SCV000254229 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-12 criteria provided, single submitter clinical testing
GeneDx RCV000425781 SCV000518147 likely benign not specified 2016-05-26 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 RCV000425781 SCV000600886 uncertain significance not specified 2016-11-23 criteria provided, single submitter clinical testing
Mendelics RCV000197376 SCV000838915 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130425 SCV000903016 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Mendelics RCV000989093 SCV001139282 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000425781 SCV001361748 likely benign not specified 2019-12-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9986A>G (p.Asn3329Ser) results in a conservative amino acid change in 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 2.4e-05 in 250776 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Furthermore, the variant has been observed in at-least one woman in a database of women who are cancer free and older than age 70 (FLOSSIES database). c.9986A>G has been reported in the literature in at-least one individual affected with Prostate cancer (Kote-Jarai_2011) and as a VUS in one family undergoing testing for the BRCA1/2 genes (Zuntini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been reported at our laboratory (BRCA2 c.1755_1759delGAAAA, p.Lys585fsX3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 (likely benign, n=3; VUS, n=3) some of whom report overlapping evidence utilized in the context of this evaluation. In six years of tracking this variant at our laboratory, no convincing evidence supporting a pathogenic outcome has been ascertained and all emerging evidence seem to point towards a likely benign outcome. Based on the evidence outlined above, the variant was re-classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289567 SCV001477524 uncertain significance none provided 2020-06-08 criteria provided, single submitter clinical testing The BRCA2 c.9986A>G; p.Asn3329Ser variant (rs76635144) is reported in the literature in a family affected with breast or ovarian cancer, but without clear evidence for disease association (Zuntini 2018). This variant is reported in ClinVar (Variation ID: 141780), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 3329 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Asn3329Ser variant is uncertain at this time. References: Zuntini R et al. Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help?. Front Genet. 2018;9:378.

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