Submissions for variant NM_007294.4(BRCA1):c.179A>G (p.Gln60Arg)

gnomAD frequency: 0.00003  dbSNP: rs373655067

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129452	SCV000184222	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	clinical testing	The p.Q60R variant (also known as c.179A>G), located in coding exon 3 of the BRCA1 gene, results from an A to G substitution at nucleotide position 179. The glutamine at codon 60 is replaced by arginine, an amino acid with highly similar properties. One functional study found that this nucleotide substitution is tolerated in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000239324	SCV000296316	uncertain significance	not specified	2016-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129452	SCV000682986	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 60 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in BARD1 binding and haploid cell proliferation assays and is at least partially functional in a ubiquitin E3 ligase assay (PMID: 25823446, 30209399). This variant has been reported in an individual affected with breast cancer (PMID: 18284688) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001729). This variant has been identified in 3/282216 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.
Invitae	RCV000637642	SCV000759109	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 60 of the BRCA1 protein (p.Gln60Arg). This variant is present in population databases (rs373655067, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 18284688, 35264596). ClinVar contains an entry for this variant (Variation ID: 141093). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 25823446, 30209399). 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.
Mendelics	RCV000637642	SCV000839314	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000239324	SCV000916707	uncertain significance	not specified	2017-10-27	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.179A>G (p.Gln60Arg) variant causes a missense change involving the alteration of a 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 3/276780 control chromosomes (gnomAD) at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)."
Brotman Baty Institute, University of Washington	RCV001075967	SCV001241629	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro