Submissions for variant NM_007294.4(BRCA1):c.1813G>C (p.Ala605Pro)

dbSNP: rs587781613

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759498	SCV000888849	uncertain significance	not provided	2018-06-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001322526	SCV001513401	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 605 of the BRCA1 protein (p.Ala605Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 619785). 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 with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824875	SCV002074221	uncertain significance	not specified	2024-02-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1813G>C (p.Ala605Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251050 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.1813G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on the ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. The following publication has been ascertained in the context of this evaluation (PMID: 32546644). ClinVar contains an entry for this variant (Variation ID: 619785). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003158102	SCV003849719	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).
Ambry Genetics	RCV003158102	SCV005550079	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-09	criteria provided, single submitter	clinical testing	The p.A605P variant (also known as c.1813G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1813. The alanine at codon 605 is replaced by proline, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.