Submissions for variant NM_007294.4(BRCA1):c.1898C>T (p.Pro633Leu)

gnomAD frequency: 0.00001  dbSNP: rs398122647

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129651	SCV000184449	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.P633L variant (also known as c.1898C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1898. The proline at codon 633 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000509321	SCV000296412	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in individuals with BRCA1-related disease in the published literature. The frequency of this variant in the general population, 0.00014 (5/34558 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001268975	SCV000698896	uncertain significance	not specified	2020-11-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1898C>T (p.Pro633Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251100 control chromosomes. 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.1898C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000637600	SCV000759066	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 633 of the BRCA1 protein (p.Pro633Leu). This variant is present in population databases (rs398122647, gnomAD 0.01%). 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: 91568). 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 with a negative predictive value of 95%. 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	RCV000129651	SCV000912046	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 633 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 5/251100 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	RCV000509321	SCV001787606	uncertain significance	not provided	2022-03-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 2017C>T; This variant is associated with the following publications: (PMID: 15343273)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129651	SCV003849657	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).
Sharing Clinical Reports Project (SCRP)	RCV000077085	SCV000108882	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-12-29	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000509321	SCV000607248	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.