ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5495C>G (p.Ser1832Cys) (rs138489917)

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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 RCV000129225 SCV000183979 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000470070 SCV000549664 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-28 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1832 of the BRCA2 protein (p.Ser1832Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs138489917, ExAC 0.03%). This variant has been observed in an individual affected with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 37969). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000031550 SCV000785291 uncertain significance Breast-ovarian cancer, familial 2 2017-06-29 criteria provided, single submitter clinical testing
Color RCV000129225 SCV001354477 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120329 SCV001362118 uncertain significance not specified 2019-12-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5495C>G (p.Ser1832Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250668 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5495C>G has been reported in the literature in sequencing studies of healthy individuals (Bodian_2014) and in individuals affected with Hereditary Breast and/or Ovarian Cancer (Singh_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031550 SCV000054155 uncertain significance Breast-ovarian cancer, familial 2 2011-10-04 no assertion criteria provided clinical testing
ITMI RCV000120329 SCV000084481 not provided not specified 2013-09-19 no assertion provided reference population

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