ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.465A>C (p.Gln155His)

dbSNP: rs864622260
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205537 SCV000259879 uncertain significance Hereditary breast ovarian cancer syndrome 2022-07-29 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 219804). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 155 of the BRCA1 protein (p.Gln155His).
GeneDx RCV000766667 SCV000293249 uncertain significance not provided 2015-10-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.465A>C at the cDNA level, p.Gln155His (Q155H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAC). Using alternate nomenclature, this variant would be defined as BRCA1 584A>C. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA1 Gln155His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln155His occurs at a position that is not conserved and is located in the BRD7 (a SWI/SNF component) interaction domain (Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Gln155His is pathogenic or benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766667 SCV000605888 uncertain significance not provided 2023-03-13 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000004 (1/251446 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a study examining personal and/or family history of breast cancer, ovarian cancer, pancreatic cancer, and/or prostate cancer (PMID: 31853058 (2020)). One functional study observed the variant to have intermediate E3 ubiquitin ligase activity (PMID: 25823446 (2015)), however further research is needed. 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.
Ambry Genetics RCV000509734 SCV000607995 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-08 criteria provided, single submitter clinical testing The p.Q155H variant (also known as c.465A>C), located in coding exon 6 of the BRCA1 gene, results from an A to C substitution at nucleotide position 465. The glutamine at codon 155 is replaced by histidine, an amino acid with highly similar properties. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236746 SCV000918760 uncertain significance not specified 2017-12-21 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.465A>C (p.Gln155His) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/246214 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000766667 SCV002048500 uncertain significance not provided 2021-07-21 criteria provided, single submitter clinical testing The BRCA1 c.465A>C; p.Gln155His variant (rs864622260), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 219804). This variant is found on a single chromosome in the Genome Aggregation Database (1/251446 alleles), indicating it is not a common polymorphism. The glutamine at codon 155 is moderately conserved, and computational analyses predict that this variant is neutral (REVEL: 0.025). Due to limited information, the clinical significance of the p.Gln155His variant is uncertain at this time.

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