Submissions for variant NM_007294.4(BRCA1):c.3267G>T (p.Leu1089Phe)

gnomAD frequency: 0.00001  dbSNP: rs767544239

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563038	SCV000673058	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-26	criteria provided, single submitter	clinical testing	The p.L1089F variant (also known as c.3267G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3267. The leucine at codon 1089 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was classified as likely benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). 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.
Color Diagnostics, LLC DBA Color Health	RCV000563038	SCV000904124	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781005	SCV000918753	uncertain significance	not specified	2017-12-28	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3267G>T (p.Leu1089Phe) variant involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in 2/276164 control chromosomes (gnomAD) at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae	RCV000814517	SCV000954930	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000563038	SCV002538194	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563038	SCV003848875	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478279	SCV004219347	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	In the published literature, it has also been characterized as being likely benign in a multifactorial likelihood study (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.0000071 (2/281884 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale case-control study, this variant has only been reported in an individual with breast cancer and none of the controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). 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.