Submissions for variant NM_007294.4(BRCA1):c.4733A>G (p.Asp1578Gly)

dbSNP: rs80356930

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130420	SCV000185283	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-01	criteria provided, single submitter	clinical testing	The p.D1578G variant (also known as c.4733A>G), located in coding exon 14 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4733. The aspartic acid at codon 1578 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol Biomarkers Prev, 2005 Jul;14:1666-71; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). 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.
Mendelics	RCV000112391	SCV001140511	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130420	SCV001352664	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 1578 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one suspected hereditary breast and ovarian cancer family (PMID: 16030099) and a multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0331 and 0.4825, respectively (PMID: 31131967). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709467	SCV001563506	likely benign	Hereditary breast ovarian cancer syndrome	2024-10-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731345	SCV001983632	likely benign	not specified	2021-09-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4733A>G (p.Asp1578Gly) 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. 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 (Cline_2019, Padilla_2019). The variant was absent in 251314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4733A>G has been reported in the literature as a VUS in at-least one individual with a personal or family history of breast and/ or ovarian cancer (example, Weitzel_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a transcriptional activation (TA) assay to determine the functional impact of missense variants coupled with VarCall, a Bayesian hierarchical model to estimate the likelihood of pathogenicity given the functional data (Woods_2016). Furthermore, multifactorial probability models predict a likely benign (IARC class 2) outcome (example, Parsons_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping but not all the evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV000112391	SCV004215111	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004804008	SCV004817635	uncertain significance	BRCA1-related cancer predisposition	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 1578 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 reported in at least one suspected hereditary breast and ovarian cancer family (PMID: 16030099) and in a multifactorial analysis that stated a family history likelihood ratio for pathogenicity of 0.4825 (PMID: 31131967). This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998171	SCV005626120	uncertain significance	not provided	2024-08-09	criteria provided, single submitter	clinical testing	The BRCA1 c.4733A>G (p.Asp1578Gly) variant has been reported in the published literature in individuals with a personal or family history of breast cancer and/or ovarian cancer (PMIDs: 35264596 (2022), 16030099 (2005)), and pancreatic cancer (PMID: 35171259 (2022)). Functional evidence suggests that this variant may impact protein function (PMID: 35196514 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112391	SCV000145169	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing