Submissions for variant NM_007294.4(BRCA1):c.733G>T (p.Asp245Tyr)

gnomAD frequency: 0.00002  dbSNP: rs147519994

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132317	SCV000187403	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-22	criteria provided, single submitter	clinical testing	The p.D245Y variant (also known as c.733G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 733. The aspartic acid at codon 245 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in a cohort of Chinese women with breast cancer (Liang Y et al. Med. Sci. Monit., 2018 Apr;24:2465-2475). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229852	SCV000289841	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 245 of the BRCA1 protein (p.Asp245Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 29681614). ClinVar contains an entry for this variant (Variation ID: 142867). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000132317	SCV000683351	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 245 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 individual affected with breast cancer (PMID: 29681614) and suspected hereditary breast and ovarian cancer families (PMID: 28726806). A multifactorial analysis reported an estimated likelihood for pathogenicity of 0.062 based on the personal and family history of two carriers (PMID: 31853058). This variant has been identified in 1/249970 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	RCV000780992	SCV000918728	uncertain significance	not specified	2023-06-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.733G>T (p.Asp245Tyr) 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 4e-06 in 249970 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.733G>T has been reported in the literature in at least one individual affected with breast cancer (example: Liang_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 29681614, 28726806). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002286705	SCV002576974	uncertain significance	not provided	2022-09-27	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; Has not been previously published as pathogenic or benign to our knowledge; Also known as 852G>T; This variant is associated with the following publications: (PMID: 29681614, 32377563, 28726806, 31853058, 29884841)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002286705	SCV003799791	uncertain significance	not provided	2022-03-30	criteria provided, single submitter	clinical testing	The BRCA1 c.733G>T; p.Asp245Tyr variant (rs147519994) is reported in the literature in a cohort of breast cancer patients (Liang 2018), and is also reported in ClinVar (Variation ID: 142867). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 245 is moderately conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.558). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Liang Y et al. Prevalence and Spectrum of BRCA1/2 Germline Mutations in Women with Breast Cancer in China Based on Next-Generation Sequencing. Med Sci Monit. 2018 Apr 23;24:2465-2475. PMID: 29681614.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132317	SCV003847983	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	RCV003998142	SCV004818417	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 245 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 at least 1 individual affected with breast cancer (PMID: 29681614). This variant has been identified in 1/249970 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.
Fulgent Genetics, Fulgent Genetics	RCV005016457	SCV005647187	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-01-07	criteria provided, single submitter	clinical testing