ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3083G>A (p.Arg1028His) (rs80357459)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031088 SCV000244332 benign Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000998
Invitae RCV000048067 SCV000076080 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000120292 SCV000108664 likely benign not specified 2018-01-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000129147 SCV000183868 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000031088 SCV000220927 likely benign Breast-ovarian cancer, familial 1 2014-12-01 criteria provided, single submitter literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000048067 SCV000297226 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-12-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129147 SCV000537499 likely benign Hereditary cancer-predisposing syndrome 2015-04-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588855 SCV000699002 benign not provided 2016-03-24 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 3/4 in silico programs predicting a "benign" outcome (SNPs&GO not captured here due to low reliability index). The variant of interest was observed in a large, broad control population, ExAC with an overall allele frequency of 21/121360 (1/5780), however, the variant is predominantly observed in the Latino population with an allele frequency of 19/11576 (1/609), which exceeds the maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Therefore, suggesting that the variant of interest is a common polymorphism specifically found in population(s) of Latino origin. In addition, the variant of interest has been found in affected individuals, with limited co-occurrence and co-segregation information but has been observed to co-occur with another BRCA1 variant, c.5165C>T (p.Ser1722Phe), which was previously classified as VUS-possibly pathogenic and with a pathogenic BRCA2 variant c.771_775delTCAAA p.Asn257_Arg259fs indicating neutrality. Furthermore, the variant of interest has been classified by multiple reputable databases and clinical laboratories via ClinVar, along with publications, Easton_2007 and Lindor_2012, all which classify the variant as "neutral/likely neutral." Therefore, taking all available lines of evidence, the variant of interest is classified as Benign.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000129147 SCV000803150 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588855 SCV000806928 likely benign not provided 2018-01-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031088 SCV001287307 benign Breast-ovarian cancer, familial 1 2018-02-15 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285257 SCV001471659 likely benign none provided 2019-11-06 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031088 SCV000053684 benign Breast-ovarian cancer, familial 1 2006-10-03 no assertion criteria provided clinical testing
ITMI RCV000120292 SCV000084444 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000031088 SCV000144630 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120292 SCV000591424 benign not specified no assertion criteria provided clinical testing The p.Arg1028 variant has been reported in the literature in 9/111500 proband chromosomes of individuals with HBOC and brain cancer, although no control chromosomes were tested to establish the frequency in the general population (Abkevich_2004, Judkins_2005a, Lindor_2012, Spitzer_2000). It has also been identified in the BIC (x13), BOCs (classified as ACMG 3), and LOVD databases. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs80357459) with a MAF score of 0.001 (1000 Genomes). This residue is not conserved in mammals and the variant amino acid Histidine (His) is present in the macaque at this position, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen, SIFT, AlignGVGD) do not predict any effect on the protein function, however, this information is not predictive enough to assume pathogenicity. Myriad reports this variant as being a "polymorphism" increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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