ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7630G>A (p.Gly2544Ser) (rs587781485)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129445 SCV000184215 likely benign Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s)
Invitae RCV000161933 SCV000211918 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2544 of the BRCA2 protein (p.Gly2544Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 141088). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000662876 SCV000785774 uncertain significance Breast-ovarian cancer, familial 2 2017-11-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656622 SCV000858442 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000656622 SCV000883515 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781086 SCV000918898 likely benign not specified 2021-04-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7630G>A (p.Gly2544Ser) 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 was absent in 250832 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7630G>A has been reported to co-occur with another pathogenic variant in BRCA1 (BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161PhefsX3) in a clinical sample in the literature (Schenk_2017) as well as in one internal sample, providing supporting evidence for its benign role. The literature report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In Homology-directed repair (HDR) activity, the variant was found to be functional (Richardson_2021). Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656622 SCV000778713 uncertain significance not provided 2017-12-07 no assertion criteria provided clinical testing

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