Submissions for variant NM_007294.4(BRCA1):c.5057A>G (p.His1686Arg)

dbSNP: rs730882166

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468314	SCV000549351	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1686 of the BRCA1 protein (p.His1686Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441, 28993434; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183179). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 23867111, 30209399). This variant disrupts the p.His1686 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12496477, 18757339, 26306726, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000483050	SCV000568402	likely pathogenic	not provided	2020-11-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired homologous recombination, embryonic growth complementation, cisplatin sensitivity, and was classified as non-functional based on a saturation genome editing assay measuring cell survival (Bouwman 2013, Findlay 2018, Bouwman 2020); Observed in individuals with breast cancer (Wen 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); Also known as c.5176A>G; This variant is associated with the following publications: (PMID: 17305420, 23867111, 28993434, 30209399, 32546644, 33087888)
Ambry Genetics	RCV000509750	SCV000607981	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-12-18	criteria provided, single submitter	clinical testing	The p.H1686R variant (also known as c.5057A>G), located in coding exon 15 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5057. The histidine at codon 1686 is replaced by arginine, an amino acid with highly similar properties. This alteration is located in the functionally important BRCT domain, and in one study was classified as deleterious based on proliferation assays and cisplatin sensitivity cDNA functional assays in mouse embryonic stem cells (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55). A different alteration located at the same position, p.H1686Q, has been reported in a individual with a personal history of breast cancer and a family history of breast and ovarian cancer (Giannini G, et al. J. Clin. Oncol. 2008;26(25):4212-4). In addition, a functional temperature sensitive study performed using yeast cells showed that p.H1686Q displayed a temperature-dependent activation of transcription when tested in human cells, indicating that this residue is located at a critical position for the stability of the BRCT domain (Carvalho MA, et al. Cancer Biol. Ther 1(5):502-8). The p.H1686R amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000483050	SCV001715194	pathogenic	not provided	2019-11-14	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM5
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483050	SCV004219435	likely pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	The BRCA1 c.5057A>G (p.His1686Arg) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 28993434 (2018), 25452441 (2015), 18757339 (2008)). Assessment of experimental evidence indicates this variant has deleterious effects on protein function (PMIDs: 30209399 (2018), 23867111 (2013)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000483050	SCV005199706	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000162048	SCV000212004	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-11	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000162048	SCV001242021	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Medical and Surgical Sciences, University of Bologna	RCV000162048	SCV004228367	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	PS3(Strong)+PM2(Supporting)+PP4(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)