ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.465A>C (p.Gln155His) (rs864622260)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205537 SCV000259879 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-08-08 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 155 of the BRCA1 protein (p.Gln155His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases and has not been published in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). However, the histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
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 RCV000236746 SCV000605888 uncertain significance not specified 2017-03-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509734 SCV000607995 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America 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.

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