ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2246A>T (p.Asp749Val)

gnomAD frequency: 0.00001  dbSNP: rs730881479
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159965 SCV000210124 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2246A>T at the cDNA level, p.Asp749Val (D749V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). Using alternate nomenclature, this variant has previously been published as BRCA1 2365A>T. This variant was observed in an individual with a family history of breast cancer, who also carried a pathogenic BRCA1 variant (Reeves 2004). This variant was also observed in an individual undergoing hereditary cancer testing, for whom a personal and/or family history was not provided (Judkins 2005). BRCA1 Asp749Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA and STAT1 binding domains (Ouchi 2000, Narod 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Asp749Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206207 SCV000261014 uncertain significance Hereditary breast ovarian cancer syndrome 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 749 of the BRCA1 protein (p.Asp749Val). This variant is present in population databases (rs730881479, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer for which a pathogenic allele was also identified in the BRCA1 gene however there was insufficient evidence to conclude whether or not these variants segregate with disease (PMID: 15146556). ClinVar contains an entry for this variant (Variation ID: 182143). 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.
Ambry Genetics RCV000571520 SCV000661047 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-19 criteria provided, single submitter clinical testing The p.D749V variant (also known as c.2246A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2246. The aspartic acid at codon 749 is replaced by valine, an amino acid with highly dissimilar properties. In one study of 90 South African breast/ovarian cancer families, this variant was observed in a family with nine cases of breast cancer and co-occurred with BRCA1 p.E881* (Reeves MD et al. Int. J. Cancer. 2004 Jul; 110(5):677-82). This alteration has also been detected in another patient from a breast and/or ovarian cancer family (Judkins T et al. Cancer Res. 2005 Nov;65(21):10096-103). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159965 SCV000888858 uncertain significance not provided 2017-09-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255547 SCV001432017 uncertain significance not specified 2021-08-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2246A>T (p.Asp749Val) 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 251204 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2246A>T has been reported in the literature in individuals affected with and/or undergoing screening for Hereditary Breast And Ovarian Cancer Syndrome (example, Reeves_2004, Judkins_2005). 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. Four 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000571520 SCV003847815 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).

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