ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4662T>G (p.Ser1554Arg) (rs276174845)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166993 SCV000217814 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077332 SCV000146465 uncertain significance Breast-ovarian cancer, familial 2 2011-10-19 no assertion criteria provided clinical testing
Color RCV000166993 SCV000911555 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-26 criteria provided, single submitter clinical testing
Counsyl RCV000077332 SCV000784939 uncertain significance Breast-ovarian cancer, familial 2 2017-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000585939 SCV000210340 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4662T>G at the cDNA level, p.Ser1554Arg (S1554R) at the protein level, and results in the change of a Serine to an Arginine (AGT>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 4890T>G. This variant has been identified in at least one individual with epithelial ovarian cancer (Cunningham 2014). BRCA2 Ser1554Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ser1554Arg is located in the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ser1554Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000585939 SCV000694793 uncertain significance not provided 2016-12-08 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4662T>G (p.Ser1554Arg) variant causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/120626, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. The variant of interest was reported in an affected individual via a publication, although with limited information (ie, lack of co-occurrence and cosegregation data). Multiple clinical diagnostic laboratories/databases cite the variant with a classification of "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000044465 SCV000072478 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 1554 of the BRCA2 protein (p.Ser1554Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs276174845, ExAC 0.002%). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51692). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The arginine 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, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000077332 SCV000109129 uncertain significance Breast-ovarian cancer, familial 2 2011-04-11 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.