ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.587G>T (p.Ser196Ile) (rs80358818)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044783 SCV000072796 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-08-04 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 196 of the BRCA2 protein (p.Ser196Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 21218378). ClinVar contains an entry for this variant (Variation ID: 51959). 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. Experimental studies have shown that this variant causes a slight increase in exon 7 skipping (PMID: 23983145), although the impact of this alteration on BRCA2 protein function was not reported. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000166163 SCV000216937 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000113840 SCV000489341 uncertain significance Breast-ovarian cancer, familial 2 2016-09-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780031 SCV000917037 uncertain significance not specified 2018-10-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.587G>T (p.Ser196Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246192 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.587G>T has been reported in the literature, however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact exon 7 skipping, however, does not allow convincing conclusions about the variant effect. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113840 SCV000147221 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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