Submissions for variant NM_007294.4(BRCA1):c.2930C>T (p.Pro977Leu)

gnomAD frequency: 0.00001  dbSNP: rs141465583

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000470122	SCV000549354	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-12	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 977 of the BRCA1 protein (p.Pro977Leu). This variant is present in population databases (rs141465583, gnomAD 0.002%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 27768182). ClinVar contains an entry for this variant (Variation ID: 409337). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 27768182). 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	RCV000575414	SCV000665827	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	The p.P977L variant (also known as c.2930C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2930. The proline at codon 977 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770745	SCV000902228	uncertain significance	Breast and/or ovarian cancer	2017-06-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575414	SCV003849242	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353611	SCV000591415	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Pro977Leu variant was not identified in the literature, nor was it identified in HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC or UMD. The variant is listed in the dbSNP database (ID#:rs141465583 ) but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined, NHLBI Exome Sequencing Project (Exome Variant Server) in 1 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 of 121118 chromosomes (frequency: 0.0000) (or 1 individual from a population of European (Non-Finnish) and none from East Asian/Other/African/Latino/South Asian/European (Finnish) individuals), increasing the likelihood this could be a low frequency benign variant. The p.Pro977 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.