ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2246A>T (p.Asp749Val) (rs730881479)

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Total submissions: 5
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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 and ovarian cancer syndrome 2019-08-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 749 of the BRCA1 protein (p.Asp749Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one family affected with breast cancer for which a pathogenic allele was also identified in the BRCA1 gene (PMID: 15146556). However, there is insufficient evidence to conclude whether or not these variants segregate with disease in that family. This variant is also known as 2365A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 182143). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000571520 SCV000661047 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing Insufficient evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159965 SCV000888858 uncertain significance not provided 2017-09-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001255547 SCV001432017 uncertain significance not specified 2020-08-24 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 Hereditary Breast And Ovarian Cancer Syndrome (Reeves_2004, Judkins_2005). These reports 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.

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