ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2274T>G (p.Ser758Arg) (rs142243359)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129440 SCV000184210 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Color RCV000129440 SCV000903888 likely benign Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
GeneDx RCV000589431 SCV000210286 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2274T>G at the cDNA level, p.Ser758Arg (S758R) 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 2502T>G. This variant has been observed in at least one case of early-onset breast cancer (Fernandes 2016). BRCA2 Ser758Arg was observed at an allele frequency of 0.03% (8/24,030) in individuals of African ancestry in large population cohorts (Lek 2016). Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ser758Arg occurs at a position that is not conserved and is not located in a known functional domain. 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 Ser758Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589431 SCV000694600 uncertain significance not provided 2016-11-11 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2274T>G (p.Ser758Arg) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 2/121206 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS, while one classified it as benign, without evidence to independently evaluate. The variant of interest has not, to our knowledge, been reported in affected individuals via publications or cited by reputable databases/clinical diagnostic laboratories. Neither was the variant evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000167883 SCV000218529 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 758 of the BRCA2 protein (p.Ser758Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs142243359, ExAC 0.02%). This variant has been reported in an individual affected with breast cancer (PMID: 27741520). ClinVar contains an entry for this variant (Variation ID: 141084). 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, 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.
Mendelics RCV000167883 SCV000838769 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing

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