Submissions for variant NM_007294.4(BRCA1):c.3392A>G (p.Asp1131Gly)

dbSNP: rs1555587813

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534135	SCV000635894	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-02-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1131 of the BRCA1 protein (p.Asp1131Gly). This missense change has been observed in individual(s) with breast cancer (PMID: 32393398). ClinVar contains an entry for this variant (Variation ID: 462608). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV001770426	SCV002004023	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469189	SCV002766357	uncertain significance	not specified	2022-11-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3392A>G (p.Asp1131Gly) results in a non-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 3.7e-06 in 273492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3392A>G has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (e.g. Sirisena_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157702	SCV003850512	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	RCV003157702	SCV005025773	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The p.D1131G variant (also known as c.3392A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3392. The aspartic acid at codon 1131 is replaced by glycine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Gunawardena K et al. BMC Res Notes, 2023 Jun;16:95). 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 alteration remains unclear.