Submissions for variant NM_007294.4(BRCA1):c.3083G>T (p.Arg1028Leu)

dbSNP: rs80357459

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165320	SCV000216042	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	The p.R1028L variant (also known as c.3083G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3083. The arginine at codon 1028 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in one Danish/Arabic kindred with familial breast cancer and in one Croatian female with familial breast-ovarian cancer (Hansen TV, Fam. Cancer 2011 Jun; 10(2):207-12, Levanat S, Gene 2012 May; 498(2):169-76). This alteration has been reported as a variant of unknown significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200747	SCV000254969	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1028 of the BRCA1 protein (p.Arg1028Leu). This variant is present in population databases (rs80357459, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 21318380, 22366370). ClinVar contains an entry for this variant (Variation ID: 185826). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. 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.
GeneKor MSA	RCV000165320	SCV000821921	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165320	SCV000909320	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1028 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 been reported in individuals with personal or family history of breast and/or ovarian cancer (PMID: 21318380, 22366370, 31159747) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005342). This variant has been identified in 1/251102 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290537	SCV001478592	uncertain significance	not specified	2021-01-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3083G>T (p.Arg1028Leu) 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 4e-06 in 251102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3083G>T has been reported in the literature in an unaffected Arabic proband (no cancer) from a family with extensive history of breast cancer (Hansen_2011), cohort of women with positive personal or family history of breast/ovarian cancer (Levanat_2012), comprehensively genotyped cohort of individuals referred for multigene panel and genomic rearrangement testing (Tsaousis_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165320	SCV003849138	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).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003321532	SCV004026307	uncertain significance	not provided	2023-03-22	criteria provided, single submitter	clinical testing	PM2_SUP
All of Us Research Program, National Institutes of Health	RCV003333739	SCV004815605	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1028 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 been reported in individuals with personal or family history of breast and/or ovarian cancer (PMID: 21318380, 22366370, 31159747) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005342). This variant has been identified in 1/251102 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.
Fulgent Genetics, Fulgent Genetics	RCV005016495	SCV005647155	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-03-28	criteria provided, single submitter	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003333739	SCV004041700	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-09	no assertion criteria provided	clinical testing