ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.326A>G (p.Asn109Ser) (rs587782734)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132232 SCV000187315 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000213770 SCV000278892 uncertain significance not provided 2017-08-30 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.326A>G at the cDNA level, p.Asn109Ser (N109S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an oral squamous cell carcinoma (India Project 2013). BRIP1 Asn109Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Asn109Ser occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRIP1 Asn109Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000687515 SCV000815087 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 109 of the BRIP1 protein (p.Asn109Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs587782734, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 142809). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Mendelics RCV000709565 SCV000839401 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000132232 SCV000903618 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Mendelics RCV000990039 SCV001140803 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing

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