Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| UOSD Diagnostica Molecolare E Genomica, |
RCV000494689 | SCV000579222 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-02-05 | criteria provided, single submitter | phenotyping only | We underline that this variant, classified as likely pathogenic, must be classified as pathogenic variant. We found this variant in two unrelated patients with familial ovarian and breast cancers. |
| Invitae | RCV000257990 | SCV000636010 | pathogenic | Hereditary breast ovarian cancer syndrome | 2020-05-26 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1706 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15689452, 23867111, 27272900, 15923272, 17308087, 11979449, 17924331). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect BRCA1 protein function (PMID: 30209399, 30458859). This variant has been observed in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 25948282, 22144684, 17262179, 27616075). This variant is also known as G602R in the literature. ClinVar contains an entry for this variant (Variation ID: 267221). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 1706 of the BRCA1 protein (p.Gly1706Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. |
| Ambry Genetics | RCV002338815 | SCV002643877 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-04-03 | criteria provided, single submitter | clinical testing | The p.G1706R variant (also known as c.5116G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5116. The glycine at codon 1706 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in many individuals diagnosed with breast and/or ovarian cancer (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Wu X et al. Int. J. Gynecol. Cancer. 2017 10;27:1650-1657; Bhaskaran SP et al. Int. J. Cancer. 2019 08;145:962-973; Gao X et al. Hum. Mutat. 2020 Mar;41:696-708). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Another study utilizing a dual luciferase TA activity assay showed that this variant had a complete lack of transactivation activity (Langerud J et al. Hum. Genomics. 2018 11;12:51). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV001353435 | SCV000591581 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | The p.Gly1706Arg variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, or BIC; nor was it identified by our laboratory. The variant was identified in UMD (10X as a causal variant) and in the Breast Cancer IARC. The p.Gly1706 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the p.Gly1706Arg (Arginine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The p.Gly1706Arg variant occurs outside of the splicing consensus sequence but 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not very predictive of pathogenicity. The p.Gly1706Arg variant is located in BRCT domains and the glycine 1706 residue maps to helix ÔÅ°2. Functional and structural studies (Karchin 2007, Carvalho 2007) that applied prediction algorithms demonstrated that the hydrophobic core is disrupted in the 1706 Arginine. Functional and structural studies classified the Gly1706Arg variant as deleterious (Carvalho 2007) and as causal (Karchin 2007) by all prediction algorithms (SIFT, UMD-Predictor, Align-GVGD, PolyPhen). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. | |
| Brotman Baty Institute, |
RCV000494689 | SCV001243567 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |