Submissions for variant NM_007294.4(BRCA1):c.5492C>G (p.Pro1831Arg)

dbSNP: rs587782778

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132312	SCV000187398	likely benign	Hereditary cancer-predisposing syndrome	2021-05-20	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508009	SCV000600426	uncertain significance	not specified	2017-04-04	criteria provided, single submitter	clinical testing
Invitae	RCV000547690	SCV000636050	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-07	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 142865). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1831 of the BRCA1 protein (p.Pro1831Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000508009	SCV000918733	uncertain significance	not specified	2019-01-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5492C>G (p.Pro1831Arg) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246012 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5492C>G in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. One publication reports experimental evidence demonstrating no damaging effect of this variant (Findlay_2018). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000132312	SCV001352262	uncertain significance	Hereditary cancer-predisposing syndrome	2019-07-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 1831 of the BRCA1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported to be functional in a haploid cell proliferation assay (PMID 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001762322	SCV001991293	uncertain significance	not provided	2019-06-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30209399)
Sema4, Sema4	RCV000132312	SCV002537865	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Brotman Baty Institute, University of Washington	RCV001076318	SCV001242043	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro