Submissions for variant NM_007294.4(BRCA1):c.124A>G (p.Ile42Val)

dbSNP: rs80357163

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175357	SCV000698840	likely benign	not specified	2023-06-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.124A>G (p.Ile42Val) results in a conservative amino acid change located in the RING-type zinc finger domain (IPR001841) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250738 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.124A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. Multiple studies have shown this variant protein retains normal activity (Ransburgh_2010, Starita_2018, Findlay_2018 Caleca_2019). At least one study showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 15235020, 30696104, 30209399, 24411079, 21725363, 24289923, 16403807, 20103620, 11320250, 30219179, 25823446, 23161852). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000775195	SCV000909421	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 42 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). Functional studies have reported that this variant does not impact BRCA1 function in a haploid cell proliferation assay, homology-directed DNA repair, ubiquitin ligase assays and in the rescue of cell survival to ionizing radiation in Brca1-null cells (PMID: 11320250, 21725363, 23161852, 30209399, 30696104). To our knowledge, this variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001398773	SCV001600548	likely benign	Hereditary breast ovarian cancer syndrome	2022-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775195	SCV002674518	likely benign	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Myriad Genetics, Inc.	RCV000083167	SCV004019715	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476945	SCV004222555	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00021 (1/4830 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Published functional studies have shown that this variant does not affect the BRCA1 function of DNA double-strand break repair (PMIDs: 30696104 (2018), 30219179 (2018), 30209399 (2018), 25823446 (2015), 23161852 (2013), 11320250 (2001), 15235020 (2004), 21725363 (2012), 20103620 (2010), 16403807 (2006)), but is deficient in the function of regulating centrosome number (PMIDs: 24288923 (2013), 23161852 (2013)). 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)	RCV000083167	SCV000115241	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083167	SCV000144379	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-03-24	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000083167	SCV001237892	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro