ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5231G>T (p.Ser1744Ile) (rs587782060)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130537 SCV000185406 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130537 SCV000906104 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing
Counsyl RCV000410002 SCV000488107 uncertain significance Breast-ovarian cancer, familial 2 2015-12-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590786 SCV000694847 uncertain significance not provided 2017-04-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5231G>T (p.Ser1744Ile) variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/120122 (1/40048), predominantly in the East Asian cohort, 3/8642 (1/2881), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant of 1/1333. A publication cites the variant in an affected individual diagnosed with diffuse large B cell lymphomas. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS), until additional information becomes available (ie, clinical and functional studies).
Invitae RCV000198995 SCV000254190 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-19 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 1744 of the BRCA2 protein (p.Ser1744Ile). The serine residue is weakly 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 individuals affected with breast cancer and ovarian cancer (PMID: 28664449, 27907908). ClinVar contains an entry for this variant (Variation ID: 141853). 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.

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