ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7876T>C (p.Trp2626Arg) (rs1060502459)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493105 SCV000581713 likely pathogenic not provided 2014-11-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7876T>C at the cDNA level, p.Trp2626Arg (W2626R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG) in exon 17. This variant was observed in at least one individual with breast cancer (Kim 2006). BRCA2 Trp2626Arg was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Trp2626Arg alters a position that is conserved across species and is located in the DNA-binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Another non-conservative missense substitution at this position, Trp2626Cys, has been observed in at least three women with a history of breast cancer and one child with Fanconi Anemia, was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, and has been showed to have impaired homologous recombination (Barber 2005, Borg 2010, Biswas 2011, Capanu 2011, Meyer 2012, Guidugli 2013). However, Biswas et al. (2011) found Trp2626Cys was able to rescue embryonic stem cell lethality although the rescued cells had reduced viability and Pruss et al. (2014) suggested that Trp2626Cys may be a lower penetrance or hypomorphic allele based on a clinical history weighting algorithm. Based on currently available information, we consider BRCA2 Trp2626Arg to be an expected pathogenic variant.
Invitae RCV000704789 SCV000833753 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 2626 of the BRCA2 protein (p.Trp2626Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast cancer (PMID: 17100994, 16949048). This variant is also known as 8104T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 429208). 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. Variants that disrupt the p.Trp2626 amino acid residue in BRCA2 have been observed in affected individuals (PMID: 16115142, 21138478, 20104584, 25085752, 21719596, 21719596). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.