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

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044272	SCV000072285	uncertain significance	Hereditary breast and ovarian cancer syndrome	2020-10-25	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	2019-02-01	criteria provided, single submitter	clinical testing	The p.I1275T variant (also known as c.3824T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 3824. The isoleucine at codon 1275 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in an Italian cohort of women with a personal and/or family history of breast cancer (D'Argenio V et al. Clin Chim Acta. 2015 Jun 15;446:221-5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000083101	SCV000786462	uncertain significance	Breast-ovarian cancer, familial 2	2018-05-07	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000132466	SCV000903954	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-15	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
Illumina Clinical Services Laboratory,Illumina	RCV001112374	SCV001270028	uncertain significance	Fanconi anemia, complementation group D1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV000083101	SCV001270029	uncertain significance	Breast-ovarian cancer, familial 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
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