Submissions for variant NM_000059.3(BRCA2):c.3824T>C (p.Ile1275Thr) (rs80358625)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044272	SCV000072285	uncertain significance	Hereditary breast and ovarian cancer syndrome	2018-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 1275 of the BRCA2 protein (p.Ile1275Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs80358625, ExAC <0.01%). This variant has been reported in an individual with a personal or family history of breast cancer (PMID: 25896959). This variant has also been observed in an individual in the Breast Cancer Information Core database (PMID: 10923033). However, in that individual, a pathogenic allele was also identified in the BRCA1 gene, which suggests that this c.3824T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51531). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000132466	SCV000187560	uncertain significance	Hereditary cancer-predisposing syndrome	2016-06-13	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl	RCV000083101	SCV000786462	uncertain significance	Breast-ovarian cancer, familial 2	2018-05-07	criteria provided, single submitter	clinical testing
Color	RCV000132466	SCV000903954	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985512	SCV001133772	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083101	SCV000115175	uncertain significance	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083101	SCV000146303	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing