ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3302A>G (p.His1101Arg) (rs398122761)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129726 SCV000184531 likely benign Hereditary cancer-predisposing syndrome 2017-12-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
Color RCV000129726 SCV000910977 likely benign Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing
Counsyl RCV000077704 SCV000489189 uncertain significance Breast-ovarian cancer, familial 2 2016-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000657002 SCV000566035 uncertain significance not provided 2017-06-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3302A>G at the cDNA level, p.His1101Arg (H1101R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 3530A>G. Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a confirmed somatic variant in colon adenocarcinoma (Guda 2015). BRCA2 His1101Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 His1101Arg occurs at a position that is not conserved and is located within the RAD51 binding domain (Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 His1101Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000483080 SCV000918842 uncertain significance not specified 2017-10-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3302A>G (p.His1101Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/225626 control chromosomes at a frequency of 0.00044%, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.075%). The variant was reported in one patient with Br/OC (Loizidou 2017), however no further information was provided on this case (i.e. no exact diagnosis, and co-occurrence or co-segregation data were included), thus limiting independent evaluation of causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000196747 SCV000254180 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1101 of the BRCA2 protein (p.His1101Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individual(s) affected with breast and/or ovarian cancer (PMID: 27882536), in an individual affected with pancreatic cancer (PMID: 28767289), and in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91796). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483080 SCV000600545 uncertain significance not specified 2017-01-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077704 SCV000109507 uncertain significance Breast-ovarian cancer, familial 2 2012-04-09 no assertion criteria provided clinical testing

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