Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222899 | SCV000275335 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-06-06 | criteria provided, single submitter | clinical testing | Lines of evidence used in support of classification: Insufficient or conflicting evidence |
| Integrated Genetics/Laboratory Corporation of America | RCV000588617 | SCV000694680 | uncertain significance | not provided | 2017-01-02 | criteria provided, single submitter | clinical testing | Variant summary: The BRCA2 c.3226G>A (p.Val1076Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant is absent in 119346 control chromosomes from ExAC. This variant has been reported in HBOC or HBOC-related families/patients and individuals undergoing BRCA1/2 testing in literature (Kote-Jarai_2011, Peixoto_2014) as well as clinical databases (UMD, ClinVar) without strong evidence for pathogenicity. In two instances, this variant was found to co-occur with other deleterious variants [BRCA2 c.3159delA (p.Asp1054IlefsX6) (UMD) and BRCA2 p.Ser871X (internal sample)], strongly suggesting for a benign outcome. Two clinical diagnostic laboratories in ClinVar have classified this variant as uncertain significance, however without evidence to independently evaluate. Taken together, this variant is classified as VUS-possibly benign. |
| Invitae | RCV000799401 | SCV000939061 | uncertain significance | Hereditary breast and ovarian cancer syndrome | 2018-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces valine with isoleucine at codon 1076 of the BRCA2 protein (p.Val1076Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family suspected to be affected with hereditary breast and/or ovarian cancer (PMID: 24916970), and an individual affected with prostate cancer (PMID: 21952622). It has also been observed in an individual referred for BRCA2 testing (PMID: 27633797). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that the c.3226G>A variant was not the primary cause of disease. In this literature, due to an apparent typographical error, these variants are indicated to occur in BRCA1 instead of BRCA2. ClinVar contains an entry for this variant (Variation ID: 96788). 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 isoleucine amino acid residue is 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 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. |
| Sharing Clinical Reports Project |
RCV000082909 | SCV000114983 | uncertain significance | Breast-ovarian cancer, familial 2 | 2012-05-01 | no assertion criteria provided | clinical testing |