ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1427A>G (p.His476Arg) (rs55720177)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082505 SCV000075486 benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130932 SCV000185844 likely benign Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown)
GeneDx RCV000120270 SCV000209924 likely benign not specified 2018-02-14 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 RCV000111616 SCV000220997 likely benign Breast-ovarian cancer, familial 1 2014-12-30 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120270 SCV000600250 likely benign not specified 2017-03-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130932 SCV000682961 likely benign Hereditary cancer-predisposing syndrome 2015-03-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589279 SCV000698865 benign not provided 2017-08-07 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1427A>G (p.His476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCA1, serine-rich domain (IPR025994) (InterPro). 3/5 in silico tools predict a damaging outcome for this variant. A functional study showed no dramatic effect on splicing for this variant (Anczukow_Genes Chromosomes and Cancer_2008). This variant was found in 34/121588 control chromosomes in the control population ExAc and in published studies, predominantly observed in the African subpopulation at a frequency of 0.00298 (31/10404). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has been reported in affected individuals via publications including one paper reporting the variant to co-occur with another deleterious BRCA1 variant, c.943ins10 (Judkins_2005) referenced in BIC, which also reports another individual with a co-occurring deleterious BRCA2 variant, c.5616_5620delAGTAA. This variant is found in two internal specimens co-occuring with pathogenic variants BRCA2 c.2957_2958insG and PMS2 c.2186_2187delTC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589279 SCV000887624 benign not provided 2018-04-24 criteria provided, single submitter clinical testing
ITMI RCV000120270 SCV000084422 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111616 SCV000144092 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 RCV000589279 SCV001550887 likely benign not provided no assertion criteria provided clinical testing The BRCA1 p.His476Arg variant was identified in 3 of 862 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and triple negative breast cancer cases; variant was not identified in 1362 control chromosomes from healthy individuals (McKean_Cowdin_2005_15726418, Rummel_2013_23192404). The variant was also identified in the following databases: dbSNP (ID: rs55720177) as “With other allele”, ClinVar (1x, as benign by Invitae, 4x as likely benign by Ambry Genetics, GeneDx, Counsyl, Quest Diagnostics, 1x as uncertain significance by BIC 1x ITMI), Clinvitae (4x, as benign and likely benign by ClinVar and Invitae), LOVD 3.0 (7x), UMD-LSDB (6 records, as neutral), BIC (9x). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer database. The variant was identified in control databases in 79 of 277056 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 70 of 24036 chromosomes (freq: 0.003), Latino in 9 of 34418 chromosomes (freq: 0.0003), while the variant was not observed in the Other, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant p.His476Arg has been reported to reside with a known deleterious mutation (BRCA1, 943ins10) (Judkins_2005_16267036). The p.His476Arg residue is not conserved in mammals and four out of five 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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