ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5244C>A (p.Ser1748Arg) (rs398122528)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569062 SCV000661221 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000569062 SCV000904995 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-25 criteria provided, single submitter clinical testing
GeneDx RCV000656796 SCV000210348 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5244C>A at the cDNA level, p.Ser1748Arg (S1748R) at the protein level, and results in the change of a Serine to an Arginine (AGC>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 5472C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser1748Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ser1748Arg occurs at a position that is not conserved and is located within the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ser1748Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000528928 SCV000635439 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 1748 of the BRCA2 protein (p.Ser1748Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91409). 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 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000076926 SCV000267779 uncertain significance Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160084 SCV000600634 uncertain significance not specified 2017-06-04 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076926 SCV000108723 uncertain significance Breast-ovarian cancer, familial 2 2010-09-29 no assertion criteria provided clinical testing

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