Submissions for variant NM_007294.4(BRCA1):c.1381T>C (p.Phe461Leu)

gnomAD frequency: 0.00001  dbSNP: rs62625300

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047448	SCV000075461	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 461 of the BRCA1 protein (p.Phe461Leu). This variant is present in population databases (rs62625300, gnomAD 0.003%). This missense change has been observed in individual(s) with prostate cancer and breast cancer (PMID: 9609997, 19638463). ClinVar contains an entry for this variant (Variation ID: 54227). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV000215677	SCV000273103	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	The p.F461L variant (also known as c.1381T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1381. The phenylalanine at codon 461 is replaced by leucine, an amino acid with highly similar properties. This alteration was previously identified in one kindred of Japanese descent with gastric and early onset breast cancer (Katagiri T et al. J. Hum. Genet. 1998; 43(1):42-8). This alteration was also identified in a high-risk breast and/or ovarian cancer family (Lu W et al. Fam Cancer, 2012 Sep;11:381-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000679681	SCV000567587	uncertain significance	not provided	2019-08-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as BRCA1 1500T>C; This variant is associated with the following publications: (PMID: 25637381, 9609997, 15235020, 16267036, 19638463, 12531920, 16518693, 10923033, 15001988, 33087888)
Color Diagnostics, LLC DBA Color Health	RCV000215677	SCV000682953	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This variant replaces phenylalanine with leucine at codon 461 in the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 9609997) and in a suspected hereditary breast and ovarian cancer family (PMID: 22476429). This variant also has been reported in an individual affected with prostate cancer (PMID: 19638463). This variant has been identified in 1/251080 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.
PreventionGenetics, part of Exact Sciences	RCV000679681	SCV000806894	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764125	SCV000895098	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679681	SCV001133485	uncertain significance	not provided	2019-03-26	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000215677	SCV003851334	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).
All of Us Research Program, National Institutes of Health	RCV000111599	SCV004818340	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-02	criteria provided, single submitter	clinical testing	This variant replaces phenylalanine with leucine at codon 461 in the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 9609997) and in a suspected hereditary breast and ovarian cancer family (PMID: 22476429). This variant also has been reported in an individual affected with prostate cancer (PMID: 19638463). This variant has been identified in 1/251080 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111599	SCV000144071	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148411	SCV000190110	uncertain significance	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679681	SCV001552161	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.F461L variant was reported in the literature in an individual with breast cancer and two individuals with prostate cancer (Katagiri_1998_PMID: 9609997, Pugh_2009_PMID: 19638463). The variant was identified in dbSNP (ID: rs62625300) and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and six other submitters). The variant was identified in control databases in 1 of 251080 chromosomes at a frequency of 0.000003983 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.F461 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on 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 uncertain significance.