ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7857G>C (p.Trp2619Cys) (rs80359011)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
School of Basic Medicine,Fourth Military Medical University RCV000664330 SCV000599883 likely pathogenic Breast-ovarian cancer, familial 2 2017-09-19 criteria provided, single submitter research This variation is identified in a proband with familial breast cancer and verified by co-segregation analysis in her family.
Ambry Genetics RCV000574330 SCV000661222 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-23 criteria provided, single submitter clinical testing The p.W2619C variant (also known as c.7857G>C), located in coding exon 16 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7857. The tryptophan at codon 2619 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in several Chinese breast and/or ovarian cancer cohorts (Yang H et al. Science, 2002 Sep;297:1837-48; Liang Y et al. Med. Sci. Monit., 2018 Apr;24:2465-2475; Li JY et al. Int. J. Cancer, 2019 01;144:281-289; Bhaskaran SP et al. Int. J. Cancer, 2019 08;145:962-973; Gao X et al. Hum. Mutat., 2019 Dec). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This alteration is considered non-functional based on data from a homology directed DNA repair assay (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000692296 SCV000820110 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 2619 of the BRCA2 protein (p.Trp2619Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with personal and/or family history of breast and/or ovarian cancer (PMID: 29681614). ClinVar contains an entry for this variant (Variation ID: 438744). 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. 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.
Color Health, Inc RCV000574330 SCV000904373 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-15 criteria provided, single submitter clinical testing

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