ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6101G>A (p.Arg2034His) (rs80358849)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166225 SCV000217004 likely benign Hereditary cancer-predisposing syndrome 2018-11-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl RCV000083122 SCV000487876 uncertain significance Breast-ovarian cancer, familial 2 2015-11-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166225 SCV000903931 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-07 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 2034 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). The presence of histidine as the reference amino acid in multiple other mammals suggests this variant may be benign. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer in the literature (PMID: 9971877, 17333343, 28435519, 30086788, 30415210), however a multifactorial likelihood analysis of breast cancer patients demonstrated a posterior probability indicating the variant is likely benign (PMID: 30415210). This variant has been identified in 1/250974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001110580 SCV001268032 uncertain significance Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000083122 SCV001268033 uncertain significance Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001374119 SCV001570896 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2034 of the BRCA2 protein (p.Arg2034His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs80358849, ExAC 0.002%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 17333343, 28435519). ClinVar contains an entry for this variant (Variation ID: 52012). 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 histidine 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ITMI RCV000120341 SCV000084493 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000083122 SCV000115196 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083122 SCV000146769 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001529429 SCV001742886 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001529429 SCV001951592 likely benign not provided no assertion criteria provided clinical testing

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