ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3848A>G (p.His1283Arg) (rs80357047)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130141 SCV000184975 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing The p.H1283R variant (also known as c.3848A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3848. The histidine at codon 1283 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000235129 SCV000210159 likely benign not specified 2017-06-30 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.
Counsyl RCV000112200 SCV000487969 uncertain significance Breast-ovarian cancer, familial 1 2015-12-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130141 SCV000909289 likely benign Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235129 SCV000918699 uncertain significance not specified 2017-09-01 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3848A>G (p.His1283Arg) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). One study (Flower_2015) based on a model of DNA methylation profiles predict the variant to be likely not pathogenic. These predictions however are not validated by functional studies. This variant was found in 2/121398 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Multiple publications, Judkins_2005 and Jimenez_2009, cites the variant in affected individuals, however, with limited information (ie, lack of cosegregation and/or co-occurrence data), therefore, evidence for causality cannot be independently validated. In addition, multiple clinical diagnostic laboratories/reputable databases have cited the variant with conflicting classifications "likely benign" or "uncertain significance." Therefore, the variant of interest has been classified as "Variant of Uncertain Significance (VUS)," until additional information becomes available (ie, clinical and functional studies).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985409 SCV001133569 uncertain significance not provided 2019-11-07 criteria provided, single submitter clinical testing
Invitae RCV001486131 SCV001690581 likely benign Hereditary breast and ovarian cancer syndrome 2020-08-16 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112200 SCV000144897 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112200 SCV000297606 likely benign Breast-ovarian cancer, familial 1 2012-08-03 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358396 SCV001554116 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.His1283Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided (Judkins 2005, Martelotto 2014). The variant was also identified in the following databases: dbSNP (ID: rs80357047) as "With other allele", ClinVar (2x likely benign, 3x uncertain significance), Clinvitae, UMD-LSDB (3x, unclassified variant), and the BIC Database (2x, clinical importance unknown). The variant was classified as a likely benign variant by the Sharing Clinical Reports Project (SCRP) (derived from Myriad reports). The variant was not identified in the COGR, Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 5 of 276850 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Latino in 1 of 34414 chromosomes (freq: 0.00003), and European in 3 of 126356 chromosomes (freq: 0.00002). The variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Studies by Judkins 2005 and Martelotto 2014 list this variant as unknown/unclassified. The p.His1283 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 uncertain significance.

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