Submissions for variant NM_007294.4(BRCA1):c.20G>A (p.Arg7His)

gnomAD frequency: 0.00001  dbSNP: rs144792613

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164210	SCV000214831	likely benign	Hereditary cancer-predisposing syndrome	2017-05-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000588310	SCV000329116	uncertain significance	not provided	2018-01-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.20G>A at the cDNA level, p.Arg7His (R7H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). Using alternate nomenclature, this variant would be defined as BRCA1 139G>A. This variant has been observed in at least one individual referred for BRCA1 testing (Judkins 2005). It was demonstrated to have E3 ligase activity and BARD1 interaction similar to wildtype and was able to rescue homology-directed repair in a cell line lacking endogenous BRCA1 (Starita 2015). BRCA1 Arg7His was not observed in large population cohorts (Lek 2016). This variant is located in the RING domain and a region known to interact with BRD7 (Harte 2010, Borg 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Arg7His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543291	SCV000635828	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 7 of the BRCA1 protein (p.Arg7His). This variant is present in population databases (rs144792613, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 184875). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 25823446, 30209399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588310	SCV000698916	uncertain significance	not provided	2017-08-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.20G>A (p.Arg7His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120706 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in at least one patient with HBOC without strong support for pathogenicity (Judkins_2005). A functional study (Starita_2015) reported the variant to be as proficient in homology-directed DNA repair as is the wild type BRCA1 indicating the variant to be in the neutral spectrum. In addition, multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Considering all evidence, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics	RCV000764129	SCV000895102	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164210	SCV000903775	likely benign	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588310	SCV002047271	likely benign	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164210	SCV002538091	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV005016488	SCV005640308	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-06-10	criteria provided, single submitter	clinical testing
Brotman Baty Institute, University of Washington	RCV001072325	SCV001237685	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Medical and Surgical Sciences, University of Bologna	RCV001072325	SCV004228312	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BS3(Strong)+BP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV001072325	SCV004244210	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-02	no assertion criteria provided	clinical testing