Submissions for variant NM_007294.4(BRCA1):c.2060A>C (p.Gln687Pro)

gnomAD frequency: 0.00002  dbSNP: rs28897680

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047696	SCV000075709	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129968	SCV000184792	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	The p.Q687P variant (also known as c.2060A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2060. The glutamine at codon 687 is replaced by proline, an amino acid with similar properties. This amino acid position is not well 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.
GeneDx	RCV000587889	SCV000565959	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2179A>C; This variant is associated with the following publications: (PMID: 16518693, 17719744, 20668451, 20167696, 25859162, 35205643, 31294896, 15385441, 31112341, 31911673, 23704879, 15343273, 31131967)
Color Diagnostics, LLC DBA Color Health	RCV000129968	SCV000683009	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 687 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected 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_000181). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 0.311, respectively (PMID: 31131967). This variant has been identified in 3/282714 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	RCV002281723	SCV000698913	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2060A>C (p.Gln687Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251304 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2060A>C has been reported in the literature as a VUS in a setting of BRCA1/2 gene panel testing at least one case of ovarian cancer, however whether the variant was germline or somatic was not determined (e.g. Ellison_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). A companion study, (Cline_2019) was also in agreement with this classification. However, to our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16518693, 31294896, 25859162, 20167696, 31112341, 15385441, 23704879). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=4; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587889	SCV002046409	uncertain significance	not provided	2023-06-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual affected with breast cancer, as well as in an unaffected control individual, in a large-scale association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)) and in an individual affected with pancreatic cancer (PMID: 35205643 (2022)). In addition, it was described as a likely benign variant in a multifactorial study (PMID: 31131967 (2019), see also LOVD (http://hci-exlovd.hci.utah.edu/)). The frequency of this variant in the general population, 0.000023 (3/129072 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 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129968	SCV003849536	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).
Mayo Clinic Laboratories, Mayo Clinic	RCV000587889	SCV004224364	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	BP1, PM2
Sharing Clinical Reports Project (SCRP)	RCV000031024	SCV000053617	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2010-03-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031024	SCV000144283	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing