Submissions for variant NM_007294.4(BRCA1):c.612G>C (p.Leu204Phe)

gnomAD frequency: 0.00003  dbSNP: rs80357394

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225767	SCV000077083	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129590	SCV000184374	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	The p.L204F variant (also known as c.612G>C), located in coding exon 8 of the BRCA1 gene, results from a G to C substitution at nucleotide position 612. The leucine at codon 204 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was detected in 1/798 individuals from a multi-center study of persons thought to be at elevated a priori risk for a BRCA1 mutation based on personal and/or family history (Shattuck-Eidens D et al. JAMA, 1997 Oct;278:1242-50). This amino acid position is well 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.
GeneDx	RCV000589445	SCV000210078	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Observed in individuals with personal and/or family history of breast and/or ovarian cancer (Shattuck-Eidens et al. 1997; Judkins et al. 2005; Flaum et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 731G>C; This variant is associated with the following publications: (PMID: 9333265, 15235020, 21309043, 16267036, 22505045, 12427538, 15385441, 32123317, 20215511, 9788437, 34663891, 36169650)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001268974	SCV000699280	likely benign	not specified	2022-11-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.612G>C (p.Leu204Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 433124 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (3.9e-05 vs 0.001), allowing no conclusion about variant significance. c.612G>C has been reported in the literature in individuals affected with breast cancer (e.g. Judkins_2005, Shattuck-Eidens_1997). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least three instances of known co-occurrences with other pathogenic variant(s) have been reported in the UMD database (BRCA2 c.8904delC, p.Val2969CysfsX7; BRCA2 c.244A>T, p.Lys82*), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on splicing, however, does not allow convincing conclusions about the variant effect on protein function although it demonstrated no effect on splicing (Houdayer_2012, Wai_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; likely benign, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation but do not capture the pathogenic co-occurrences ascertained herein. Based on the evidence outlined above, the variant retained its classification as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000589445	SCV000806980	uncertain significance	not provided	2017-07-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589445	SCV000888959	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	The BRCA1 c.612G>C (p.Leu204Phe) variant has been reported in the published literature in at least one individual at high risk of hereditary breast and/or ovarian cancer in the published literature (PMIDs: 16267036 (2005) and 22505045 (2012)). Functional assays indicated that this variant does not affect normal mRNA splicing (PMIDs: 34663891 (2021), 22505045 (2012)). The frequency of this variant in the general population, 0.0001 (13/128864 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Color Diagnostics, LLC DBA Color Health	RCV000129590	SCV000911052	likely benign	Hereditary cancer-predisposing syndrome	2017-11-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001268974	SCV002551046	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: BP1_strong
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005237484	SCV005882921	likely benign	Inherited breast cancer and ovarian cancer	2024-10-21	criteria provided, single submitter	clinical testing	BS1_Strong,BP1
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112753	SCV000145642	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-03-24	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112753	SCV004244154	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing