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

gnomAD frequency: 0.00066  dbSNP: rs55720177

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082505	SCV000075486	benign	Hereditary breast ovarian cancer syndrome	2024-01-24	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	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	RCV000589279	SCV000209924	likely benign	not provided	2021-05-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12531920, 25348012, 24728327, 15829246, 16267036, 15235020, 15726418, 22811390, 23192404, 22516946, 26913838, 18273839, 25782689, 16518693, 27527004, 15385441)
Counsyl	RCV000111616	SCV000220997	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-12-30	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	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	2022-07-01	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001082505	SCV002026002	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120270	SCV002070489	likely benign	not specified	2021-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130932	SCV002538027	likely benign	Hereditary cancer-predisposing syndrome	2021-03-02	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002477163	SCV002801713	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-11-11	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, susceptibility to, 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.