Submissions for variant NM_007294.4(BRCA1):c.3625T>G (p.Leu1209Val)

gnomAD frequency: 0.00001  dbSNP: rs273900711

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048260	SCV000076273	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1209 of the BRCA1 protein (p.Leu1209Val). This variant is present in population databases (rs273900711, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or lung cancer (PMID: 17972177, 28222693, 29625052). ClinVar contains an entry for this variant (Variation ID: 54942). 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. 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	RCV000130630	SCV000185506	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.L1209V variant (also known as c.3625T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 3625. The leucine at codon 1209 is replaced by valine, an amino acid with highly similar properties. In one study of high risk breast cancer patients in Indonesia, this variant was detected in an individual diagnosed with breast cancer at 32 years of age (Purnomosari D et al. Breast Cancer Res Treat, 2007 Dec;106:297-304). In a large case-control study using multi-ethnic Asian cohorts, this variant was detected in 1/2058 breast cancer patients and 2/1461 healthy controls (Lai KN et al. BMC Cancer, 2017 02;17:149). This alteration was also identified in two individuals diagnosed with cancer who underwent next generation sequencing (Huang KL et al. Cell, 2018 04;173:355-370.e14). This amino acid position is highly 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	RCV000130630	SCV001352968	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1209 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer and in two unaffected individuals (PMID: 17972177, 28222693) and in an individual affected the urothelial carcinoma (PMID: 29625052). This variant also has been detected in a breast cancer case-control meta-analysis in 8/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002448). This variant has also been identified in 2/251266 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	RCV001251417	SCV001427007	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3625T>G (p.Leu1209Val) results in a 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 8e-06 in 251266 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3625T>G has been reported in the literature in individuals affected with Breast Cancer (example, Purnomosari_2007, Lai_2017). 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. Three 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001251417	SCV002760936	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130630	SCV003846552	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).
GeneDx	RCV003226902	SCV003923844	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Published functional studies suggest a neutral effect: demonstrates homologous recombination repair similar to wild type (Bouwman et al., 2020); Identified in individuals with breast or other cancer, and also in unaffected controls (Purnomosari et al., 2007; Lai et al., 2017; Huang et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3744T>G; This variant is associated with the following publications: (PMID: 17972177, 28222693, 32377563, 29884841, 31853058, 32546644, 29625052)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003226902	SCV004219363	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251266 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 28222693 (2017), 17972177 (2007), 31835058 (2020), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)) and unaffected individuals (PMIDs: 28222693 (2017) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)), as well as individuals with urothelial carcinoma and lung squamous cell carcinoma (PMID: 29625052 (2018)). Use of in silico models and likelihood ratios show conflicting results. Some studies predict the variant is non-pathogenic (PMID: 33087888 (2021)), while others predict it is pathogenic (PMID: 29625052 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000077553	SCV000109354	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-10-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077553	SCV000144815	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-18	no assertion criteria provided	clinical testing