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

gnomAD frequency: 0.00001  dbSNP: rs80357047

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130141	SCV000184975	likely benign	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
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, susceptibility to, 1	2015-12-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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 ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130141	SCV003851224	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112200	SCV000144897	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112200	SCV000297606	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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.