Submissions for variant NM_007294.4(BRCA1):c.1259A>G (p.Asp420Gly)

gnomAD frequency: 0.00002  dbSNP: rs730881442

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159846	SCV000209889	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	Observed in individuals with breast or pancreatic cancer, but also in unaffected controls (PMID: 32980694, 33471991); 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 1378A>G; This variant is associated with the following publications: (PMID: 31851867, 32438681, 30122538, 32980694, 33471991, 32195105, 9582019, 9926942, 10426999, 15343273, 20215511, 29884841, 32377563, 20960228)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204508	SCV000260519	benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214615	SCV000275439	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-22	criteria provided, single submitter	clinical testing	The p.D420G variant (also known as c.1259A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1259. The aspartic acid at codon 420 is replaced by glycine, an amino acid with similar properties. This variant has been identified in an individual diagnosed with breast and/or ovarian cancer (Santonocito C et al. Cancers (Basel), 2020 May;12:). This variant was present in 2/1005 Japanese pancreatic cancer patients and in 0/23705 controls (Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). 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.
Counsyl	RCV000409308	SCV000488029	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515362	SCV000611443	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214615	SCV000682943	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 420 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with early onset breast cancer (doi: 10.5505/aot.2021.25348). This variant has been identified in 1/250816 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	RCV000779906	SCV000916814	uncertain significance	not specified	2021-03-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1259A>G (p.Asp420Gly) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250816 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1259A>G has been reported in the literature in individuals affected with breast cancer (example, Laitman_2011, Chen_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159846	SCV001133480	uncertain significance	not provided	2019-11-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159846	SCV002048576	uncertain significance	not provided	2021-08-14	criteria provided, single submitter	clinical testing	The BRCA1 c.1259A>G; p.Asp420Gly variant (rs730881442) is reported in the literature in an individual affected with breast cancer, although its clinical significance was considered uncertain (Chen 2020). This variant is found on a single chromosome in the Genome Aggregation Database (1/250816 alleles), indicating it is not a common polymorphism. The aspartate at codon 420 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.586). Due to limited information, the clinical significance of the p.Asp420Gly variant is uncertain at this time. References: Chen Q et al. BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis. Adv Sci (Weinh). 2020 Feb 14;7(6):1903616. PMID: 32195105.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000214615	SCV003846063	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).
All of Us Research Program, National Institutes of Health	RCV000409308	SCV004818351	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 420 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with early onset breast cancer (doi: 10.5505/aot.2021.25348). This variant has been identified in 1/250816 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.