ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3494A>G (p.His1165Arg) (rs587782201)

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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 RCV000130862 SCV000185761 likely benign Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Invitae RCV000230802 SCV000283213 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1165 of the BRCA2 protein (p.His1165Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs587782201, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142054). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Counsyl RCV000410985 SCV000488852 uncertain significance Breast-ovarian cancer, familial 2 2016-07-11 criteria provided, single submitter clinical testing
GeneDx RCV000483928 SCV000565752 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3494A>G at the cDNA level, p.His1165Arg (H1165R) 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 3722A>G. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA2 His1165Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 His1165Arg occurs at a position that is not conserved and is located in 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 His1165Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000130862 SCV000688809 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779959 SCV000916918 uncertain significance not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3494A>G (p.His1165Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276588 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.8e-05 vs 0.00075), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3494A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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