Submissions for variant NM_007294.4(BRCA1):c.2663A>C (p.His888Pro)

dbSNP: rs876658843

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213188	SCV000274617	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-09	criteria provided, single submitter	clinical testing	The p.H888P variant (also known as c.2663A>C and 2782A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2663. The histidine at codon 888 is replaced by proline, an amino acid with some similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000764122	SCV000895095	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
Invitae	RCV001051347	SCV001215494	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 888 of the BRCA1 protein (p.His888Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 230920). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000213188	SCV001734490	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 888 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251068 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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	RCV001589144	SCV001822862	uncertain significance	not provided	2019-06-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency 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
University of Washington Department of Laboratory Medicine, University of Washington	RCV000213188	SCV003851002	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).