Submissions for variant NM_000059.4(BRCA2):c.7857G>C (p.Trp2619Cys)

dbSNP: rs80359011

Total submissions: 5

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, susceptibility to, 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	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-12	criteria provided, single submitter	clinical testing	The p.W2619C pathogenic mutation (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 variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). Two other alterations at the same codon, p.W2619G (c.7855T>G) and p.W2619R (c.7855T>C), have also been found to be non-functional in a homology-directed DNA repair (HDR) assay and have been reported as either likely pathogenic or pathogenic by our laboratory (Ambry internal data). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692296	SCV000820110	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-08	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 29681614, 29752822, 30702160). ClinVar contains an entry for this variant (Variation ID: 438744). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 33609447). 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. This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 2619 of the BRCA2 protein (p.Trp2619Cys).
Color Diagnostics, LLC DBA Color Health	RCV000574330	SCV000904373	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-15	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV000664330	SCV004243785	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing