Submissions for variant NM_007294.4(BRCA1):c.1868T>C (p.Leu623Pro)

gnomAD frequency: 0.00001  dbSNP: rs397508915

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486928	SCV000564722	uncertain significance	not provided	2018-07-06	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1868T>C at the cDNA level, p.Leu623Pro (L623P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). This variant, also defined as BRCA1 1987T>C using alternate nomenclature, was observed in a woman with a personal and family history of early-onset breast cancer (Maillet 2006). BRCA1 Leu623Pro was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu623Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics	RCV000709485	SCV000839278	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000709485	SCV001502861	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 623 of the BRCA1 protein (p.Leu623Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 16875939). This variant is also known as c.1987T>C. ClinVar contains an entry for this variant (Variation ID: 54373). 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.
Ambry Genetics	RCV002408552	SCV002721043	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	clinical testing	The p.L623P variant (also known as c.1868T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1868. The leucine at codon 623 is replaced by proline, an amino acid with similar properties. This alteration, designated as 1987T>C (L623P), was previously identified in a Swiss patient diagnosed with breast cancer at age 37 whose mother had bilateral breast cancer diagnosed at ages 47 and 57; co-segregation studies could not be performed for this family. In that same study, this alteration was not identified in any control samples (Maillet P et al. Cancer Genet. Cytogenet. 2006 Aug;169:62-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002408552	SCV003849679	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).