Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000222899 | SCV000275335 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-09-19 | criteria provided, single submitter | clinical testing | The p.V1076I variant (also known as c.3226G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 3226. The valine at codon 1076 is replaced by isoleucine, an amino acid with highly similar properties. 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. |
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 | 2020-08-06 | 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. |
Illumina Clinical Services Laboratory, |
RCV000082909 | SCV001271420 | uncertain significance | Breast-ovarian cancer, familial 2 | 2017-04-27 | 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, |
RCV001113630 | SCV001271421 | uncertain significance | Fanconi anemia, complementation group D1 | 2017-04-27 | 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. |
Sharing Clinical Reports Project |
RCV000082909 | SCV000114983 | uncertain significance | Breast-ovarian cancer, familial 2 | 2012-05-01 | no assertion criteria provided | clinical testing |